Inclusion Criteria:  Patients with severe SCD who are 10-25 years old and are willing to donate autologous HSCs for advancing future gene therapy for SCD. Parents/legal guardians of participants must be able and willing to consent for their participation in this study. Severe SCD, for the purpose of this study, will be defined as patients who are receiving chronic transfusion therapy due to SCD related complications. The need for undergoing chronic transfusion therapy must be determined by the primary hematologist. Some patients may continue to receive hydroxyurea in addition to and simultaneously with blood transfusion therapy. Such patients are eligible for inclusion on the study if they hold hydroxyurea for at least 4 weeks. The ability to hold hydroxyurea (or not) with ongoing chronic transfusion therapy will be made by the primary hematologist as well. All genotypes of SCD will be eligible. Adequate renal function: serum/plasma creatinine < 1.5 mg/dL and creatinine clearance > 50 mL/min (as calculated by the Crockcroft-Gault formula). Adequate liver function: direct bilirubin < 2.5 times the upper limit of normal range, AST and ALT < 5 times the upper limit of normal range. Blood counts: WBC > 3,000/mm^3, granulocytes > 1,000/mm^3, hemoglobin > 7.0 g/dL, platelets > 150,000/mm^3. Female patients of childbearing age should have a negative serum pregnancy test within one week of beginning plerixafor administration, have had a hysterectomy, be post-menopausal. Negative serologic tests for syphilis, hepatitis B and C, HIV, and HTLV-1/II. Participants should either have a central line in place or be able to undergo apheresis without the necessity of the insertion of a central venous catheter Participants of childbearing potential should agree to use of an effective form of contraception during treatment and for at least 1 week after the last dose of plerixafor. ECOG performance status/Karnofsky score/Lansky score >80.  Exclusion Criteria:  Pregnancy. Female patients of childbearing age should have a negative serum pregnancy test within one week of beginning plerixafor administration, except those that have had a hysterectomy, or are post-menopausal. Active viral, bacterial, fungal, or parasitic infection. History of cancer, excluding squamous carcinoma of the skin and cervical carcinoma in situ. Active and painful splenomegaly or splenomegaly (size greater than upper limit of normal) or splenic sequestration determined by ultrasound. Previous history of splenomegaly or splenic sequestration, unless HbS level of <30% is documented within 48-72 hours of each plerixafor dose Allergy to plerixafor. Patients receiving hydroxyurea will not be included in the study. However, they may be included if the primary hematologist determines that hydroxyurea can be safely discontinued for at least 4 weeks prior to the plerixafor administration and apheresis. Generally, patients receiving chronic transfusion therapy can safely discontinue hydroxyurea therapy as there is unlikely to be any added benefit, but this will be determined by the primary treating hematologist. Poor cardiac function, as defined by an ejection fraction < 40%. History of clinically proven pulmonary hypertension. Emergency room admission or hospitalization in the past 14 days prior to first dose of study drug. Major surgery in the past 30 days prior to first dose of study drug.