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                                                                   EXHIBIT 10.1


                                 March 31, 2003

VIA FEDERAL EXPRESS
Dr. Robert J. Lefkowitz
Duke University Medical Center
Box 3821
Durham, North Carolina 27710

Dear Bob:

         We are delighted that you, an investigator of the Howard Hughes Medical
Institute (the "Institute") at the Institute's laboratory at Duke University
("Duke"), will be able to provide consulting services to Lexicon Genetics
Incorporated (which, together with its subsidiaries and affiliates, is referred
to as the "Company" or "Lexicon"). The purpose of this letter agreement (this
"Agreement") is to set forth our mutual understanding of the terms and
conditions of your service as consultant to the Company, as set forth below.

         1. Consulting Services. Under this agreement, you will provide such
consulting and advisory services as may be requested by Arthur T. Sands, M.D.,
Ph.D., the Company's President and Chief Executive Officer, relating to: (i)
evaluation of the Company's drug discovery and development programs; (ii)
identification of key personnel, consultants and service providers to assist in
the Company's drug discovery and development efforts; (iii) provision of
assistance and advice relating to the establishment of drug discovery
collaborations and alliances; and (iv) such other consulting and advisory
services relating to the Company's drug discovery and development efforts as you
and the Company may agree. We agree, however, that your consulting and advisory
services shall be limited to the exchange of ideas only, and that you shall not
direct or conduct research for or on behalf of the Company. You will devote up
to 10 days annually (inclusive of your time attending scientific review meetings
held on the day prior to meetings of the Company's Board of Directors) to
providing services to the Company under this Agreement, on a schedule and at
times mutually agreed upon by you and Dr. Sands. Your services will be rendered
by means of correspondence, telephone calls, submitted reports, information,
visits and by other means and manner as may be reasonably requested by Dr. Sands
and agreed to by you.

         2. Compensation. As full consideration for your services as a
consultant to the Company and your obligations under this Agreement, you will
receive fees of $50,000 per year, payable in 12 monthly installments. In
addition, you will be reimbursed for your reasonable, ordinary and necessary
travel expenses incurred by you at the Company's prior request in connection
with your performance of your services under this Agreement.

         3. Confidential Information.

             (a) In the course of your services for the Company, you may learn
         or be exposed, orally, visually, electronically or in writing, to
         inventions, discoveries, improvements, materials, data, technology,
         processes, formulas, know-how, trade secrets, ideas and other
         information which we consider proprietary or confidential
         ("Confidential

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Dr. Robert J. Lefkowitz
March 31, 2003
Page 2


         Information"). You agree to hold any Confidential Information
         disclosed to you by the Company or learned by you from the Company in
         conjunction with your services for the Company in strict confidence and
         to take all reasonable precautions to protect such Confidential
         Information, not to disclose any such Confidential Information to any
         third party, and to use such Confidential Information only in
         furtherance of your service as an Advisory Panel member; provided that
         your nondisclosure obligation shall not apply to the extent such
         Confidential Information (i) is already in the public domain or
         hereafter enters the public domain other than through your acts or
         omissions in violation of this Agreement; (ii) is already known to you,
         as may be shown by competent written records; and (iii) is hereafter
         received by you without restriction as to confidentiality or use from a
         third party lawfully entitled so to disclose same in such manner.
         Information shall not be deemed to be within the foregoing exceptions
         merely because such information is embraced by more general information
         in the public domain or in your possession. Information generated by
         you, alone or with others, shall not constitute Confidential
         Information subject to the foregoing restrictions unless that
         information (x) is generated solely as a direct result of the
         performance of your services under this Agreement and (y) is not
         generated in the course of the your activities as an employee of the
         Institute or as a Duke faculty member. All Confidential Information
         (and any copies and notes thereof) shall remain the sole property of
         the Company.

             (b) You agree not to disclose or otherwise make available to the
         Company any information that you possess under an obligation of
         confidentiality to a third party. You may disclose to the Company any
         information that you would normally freely disclose to other members of
         the scientific community at large, whether by publication, by
         presentation at seminars or in informal scientific discussions.
         However, you shall not disclose to us information that is proprietary
         to the Institute or Duke and is not generally available to the public
         other than through formal technology transfer procedures.

             4. Inventions and Discoveries.

             (a) You hereby assign and transfer to the Company all of your
         right, title and interest throughout the world in all inventions,
         discoveries, improvements and other intellectual property, whether or
         not patentable or subject to copyright, which may be made, written or
         conceived by you, alone or with others, (i) solely as a direct result
         of the performance of your services for the Company under this
         Agreement and (ii) not in the course of your activities as an Institute
         employee or Duke faculty member (collectively, "Lexicon Intellectual
         Property"). All such Lexicon Intellectual Property shall be the sole
         property of the Company or its nominee. The Company agrees that it
         shall have no rights by reason of this Agreement in any inventions,
         discoveries, improvements or other intellectual property, whether or
         not patentable or subject to copyright, which may be made, written or
         conceived by you, alone or with others, in the course of your
         activities as an Institute employee or Duke faculty member or as a
         result of a program of research financed, in whole or in part, by funds
         provided by or under the control of the Institute or Duke. The Company
         further acknowledges and agrees that it will enjoy no priority or
         advantage as a result of the consultancy created by this Agreement in
         gaining access, whether by license or otherwise, to any proprietary
         information or intellectual property that arises from any research you
         undertake in your capacity as an Institute employee or Duke faculty
         member.

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Dr. Robert J. Lefkowitz
March 31, 2003
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             (b) You shall promptly disclose any Lexicon Intellectual Property
         in writing to the Company in order to permit the Company to claim
         rights to which it may be entitled under this Agreement. The Company
         shall have full power and authority to file and prosecute patent
         applications and copyright registrations throughout the world with
         respect to all Lexicon Intellectual Property, and to procure and
         maintain patents and copyrights with respect thereto. You agree, at the
         Company's reasonable request and expense, to sign, execute and
         acknowledge, or cause to be signed, executed and acknowledged, any
         applications, assignments, instruments and other documents, and to
         perform such other acts, as the Company may deem necessary, useful or
         convenient to confirm and vest in the Company or its nominee all right,
         title and interest throughout the world in and to any Lexicon
         Intellectual Property and all patent, copyright and other intellectual
         property rights and protections therein, and to assist the Company in
         procuring, maintaining, enforcing and defending such patent, copyright
         and other intellectual property rights and protections throughout the
         world. You agree to treat all such Lexicon Intellectual Property as
         Confidential Information under this Agreement.

             5. Indemnification.

             (a) The Company agrees, at its sole expense, to defend you, the
         Institute and Duke against, and to indemnify and hold you, the
         Institute and Duke, and their respective trustees, directors, officers,
         employees, and agents (collectively, "Indemnitees") harmless from, any
         liability, claim, judgment, cost, expense, damage, deficiency, loss, or
         obligation, of any kind or nature (including without limitation
         reasonable attorneys' fees and other costs and expenses of defense)
         relating to a claim or suit by a third party against you, the
         Institute, or Duke, or any liabilities or judgments based thereon,
         either arising from this Agreement, your performance of services for
         the Company under this Agreement, or any products or services of the
         Company which result from your services under this Agreement
         ("Claims"); provided, however, that the Company shall have no
         obligation to indemnify you for any liability, damage, loss or expense
         to the extent that it is attributable to: (i) your negligent or
         wrongful acts or omissions, reckless misconduct or intentional
         misconduct; (ii) your failure to comply with the terms of this
         Agreement; (iii) your failure to comply with applicable governmental or
         legal requirements; (iv) any breach by you of a contractual or
         fiduciary obligation owed to a third party; and/or (v) misappropriation
         of trade secrets by you.

             (b) As a condition precedent to Lexicon' obligations under Section
         5(a) above, each affected Indemnitee must:

                (i) reasonably promptly following actual receipt of written
             notice thereof by you (in the case of a Claim against you) or by an
             officer or attorney of any other Indemnitee (in the case of a Claim
             against such other Indemnitee), you or any other Indemnitee (as the
             case may be) will notify the Company in writing of any such Claim
             for which such Indemnitee intends to seek indemnification under
             Section 5(a) above; provided, however, that the delay or failure of
             an Indemnitee to give reasonably prompt notice to the Company of
             any Claim shall not affect the Indemnitee's rights unless, and then
             only to the extent that, such delay or failure is prejudicial to or
             otherwise adversely affects the Company;

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Dr. Robert J. Lefkowitz
March 31, 2003
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                (ii)  permit and authorize the Company to conduct and exercise
             sole control of the defense and disposition of any such Claim
             (including, without limitation, all decisions to litigate, settle
             or appeal) and to represent the Indemnitee in connection therewith
             (and, as necessary and if prior written notice is given to the
             Indemnitee and the Indemnitee consents to the use of Indemnitee's
             name, which consent shall not unreasonably be withheld, to use such
             Indemnitee's name in connection with such defense and disposition);
             and

               (iii)  cooperate with the Company in the handling of any such
             Claim by providing and permitting the Company reasonable access to
             and copies of pertinent records and documents and by making
             themselves (and other relevant individuals whom an Indemnitee may
             control) reasonably available for interview and testimony.

         Subject to the foregoing: (x) the Company agrees, at its own expense,
         to provide attorney(s) to defend against any such Claims, whether or
         not such actions are rightfully brought (the Company agrees to select
         attorneys reasonably acceptable to any Indemnitee), (y) the Company
         will pay all costs necessary to defend against such Claims, and (z) an
         Indemnitee may, at its/his/her own expense, participate in any such
         Claim using attorneys of its/his/her choice. In no event may any
         Indemnitee settle any such Claim for which it/he/she intends to seek
         indemnification from the Company hereunder without the Company's prior
         written consent, to be given or withheld in the Company's discretion.
         The Company agrees not to settle any Claim against an Indemnitee
         without such Indemnitee's written consent, where such settlement would
         include any admission of liability on the part of the Indemnitee or
         where the settlement would impose any restriction on the Indemnitee's
         conduct of its/his/her activities or where such settlement would not
         include an unconditional release of the Indemnitee from all liability
         for claims that are the subject matter of the settled Claim.

         6. Term and Termination. You will render your advisory and consulting
services to the Company for an initial period of one year commencing upon the
date of your signature accepting the provisions of this Agreement on the
signature page. The term of this Agreement shall be automatically renewed for
additional one-year terms on each anniversary unless either party gives 30 days'
advance written notice of non-renewal. This Agreement may be terminated (i) at
any time by either party, with or without cause, upon 30 days' advance written
notice to the other party and (ii) by either party for breach of this Agreement
by the other party that, where curable, is not cured within 10 business days
after written notice of such breach is delivered to the breaching party.

         7. Independent Contractor. For purposes of this Agreement, you will be
deemed an independent contractor and not an employee or agent of the Company. In
this connection, you will not be eligible for, nor entitled to, any employee
benefits that we normally extend to our employees, and we will not withhold any
taxes from the compensation paid to you, all of which shall be your
responsibility. The manner in which you render your services under this
Agreement will be within your reasonable control and discretion. You have no
express or implied authority to incur any liability, or to make any decision or
to create any binding obligation, on our behalf.

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Dr. Robert J. Lefkowitz
March 31, 2003
Page 5


         8. Reference to Affiliation. The Company may use your name, and in
doing so may make reference to your affiliation with the Institute and Duke, so
long as any such usage is limited to reporting factual events or occurrences
(including your relationship with the Company) and is made in a manner that
could not reasonably constitute an endorsement of the Company or of any of its
programs, products or services. However, the Company shall not use your name or
the name of the Institute or Duke in any press release, quote you in any Lexicon
materials, or otherwise use your name or the name of the Institute or Duke in a
manner not specifically permitted by the preceding sentence, unless in each case
the Company obtains your consent and the advance written consent of the
Institute or Duke, as applicable.

         9. Compliance with Laws and Procedures. To the extent you provide your
services under this Agreement on our premises, you agree to observe our business
hours, as well as our rules, policies and security procedures concerning conduct
and the health, safety and protection of persons and property. You will comply
with all applicable governmental laws, ordinances, rules and regulations
applicable to the performance of your services under this Agreement. The Company
acknowledges that you are an employee of the Institute and a faculty member of
Duke and are subject to the Institute and Duke's policies, including policies
concerning consulting, conflicts of interest, and intellectual property.

         10. No Implied Grants, Options, or Licenses. Except for the express
provisions contained herein, nothing in this Agreement shall be deemed as
constituting, a grant, option, license, or sublicense to make, use, sell,
disclose, or otherwise disseminate any of the Company's patents, Confidential
Information or other intellectual property presently in force or existence, or
which may be acquired by, issued to, granted upon, invented by, licensed or
sublicensed by the Company at a future date.

         11. Governing Law. This Agreement shall be governed by, and construed
and enforced in accordance with, the laws of the State of Texas as they apply to
contracts entered into and wholly to be performed in Texas.

         12. Enforcement. You agree that a breach of any of the restrictions set
forth in the provisions of this Agreement would cause the Company irreparable
injury and damage, and that, in the event of any breach or threatened breach,
the Company, in addition to all other rights and remedies at law or in equity,
shall have the right to enforce the specific performance of such restrictions
and to apply for injunctive relief against their violation.

         13. Survival of Terms. The provisions of Sections 3, 4, 5 and 11
through 20 hereof shall survive termination of this Agreement.

         14. Successors and Assigns. You may not assign this Agreement without
the written consent of the Company. This Agreement shall be binding on your
heirs, executors, administrators and legal representatives and the Company's
successors and assigns.

         15. Severability. The invalidity or unenforceability of any provision
of this Agreement (or portion thereof) shall not affect the validity or
enforceability of any other provision of this Agreement, and if such provision
(or portion thereof) is so broad as to be unenforceable, it shall be interpreted
to be only as broad as is enforceable; provided that, if any provision of this
Agreement affecting the rights or property of the Institute is adjudicated to be

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Dr. Robert J. Lefkowitz
March 31, 2003
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invalid, unenforceable, contrary to or prohibited under applicable laws or
regulations of any jurisdiction, this Agreement shall terminate as of the date
such adjudication is effective.

         16. Entire Agreement. This Agreement constitutes the sole and complete
agreement of the parties with respect to the matters included herein, and
supersedes any previous oral or written agreement, if any, relating to the
subject matters included herein.

         17. Amendment and Waiver. This Agreement may not be amended or
supplemented in any way, nor may the benefit of any provision hereof be waived,
except by a written agreement duly executed by both you and the Company. The
Company and you acknowledge and agree that any amendment of this Agreement
(including, without limitation, any change from the terms of Section 2 in the
consideration to be provided to you with respect to services to be provided
hereunder or any extension of this Agreement other than as set forth in Section
6) or any departure from the terms or conditions hereof with respect to your
services for the Company is subject to the Institute's prior written approval.

         18. No Conflict. You represent that you have the right under the terms
of your relationship with the Institute and Duke to enter into and perform this
Agreement, and that the performance of your obligations and duties under this
Agreement does not conflict with the Institute or Duke's policies or with any
obligations or duties, express or implied, that you may have to third parties.
You further represent that you have provided a copy of this Agreement to the
Institute and that the Institute has provided written confirmation to you that
this Agreement does not violate its policies. We acknowledge and agree that
nothing in this Agreement shall affect your obligations to, or research on
behalf of, the Institute or Duke, including, without limitation, your
obligations or research in connection with a transfer by the Institute or Duke
of materials or intellectual property developed in whole or in part by you, or
in connection with research collaborations.

         19. Individual Capacity; Third Party Beneficiary. You and the Company
acknowledge that (i) you are entering into this Agreement in your individual
capacity and not as an employee or agent of the Institute, (ii) the Institute is
not a party to this Agreement and has no liability or obligation hereunder, and
(iii) the Institute is an intended third-party beneficiary of this Agreement and
certain provisions of this Agreement are for the benefit of the Institute and
are enforceable by the Institute in its own name.

         20. Construction. Each party to this Agreement has had the opportunity
to review this Agreement with legal counsel. This Agreement shall not be
construed or interpreted against any party on the basis that such party drafted
or authored a particular provision, parts of or the entirety of this Agreement.

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Dr. Robert J. Lefkowitz
March 31, 2003
Page 7


         If the foregoing correctly sets forth our mutual understanding, please
so indicate by signing this letter in the space provided below and return it to
the Company at the above address, whereupon this Agreement shall constitute a
binding contract between us and our legal representatives, successors, and
assigns.

                                  Very truly yours,

                                  LEXICON GENETICS INCORPORATED


                                   By:  /s/ Arthur T. Sands
                                        -------------------------------------
                                        Arthur T. Sands, M.D., Ph.D.
                                        President and Chief Executive Officer


ACCEPTED AND AGREED TO AS OF THE DATE SET FORTH BELOW:


By:  /s/ Robert J. Lefkowitz, M.D.
     -----------------------------
     Robert J. Lefkowitz, M.D.

Social Security No.:
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Date:  March 31, 2003