Only a fraction of smokers receive information about effective prescription-only smoking pharmacotherapies, bupropion and varenicline. Moreover, studies have demonstrated variable smoking cessation treatment outcomes correlate with individuals' genotypes and phenotypes. Mass distribution approaches, bypassing clinics and physicians, have been successful for nicotine replacement therapy. The primary objective of this study is to evaluate the real-world long-term effectiveness of mailed bupropion and varenicline treatment in a sample of interested smokers, utilizing web-based recruitment and follow-up. As part of the Genetics Sub-study, the pharmacogenetics of these smoking cessation medications is investigated. This is an open label study, wherein eligible participants will be randomized to receive bupropion (Zyban®) or varenicline (Champix®) for 12 weeks in conjunction with weekly motivational emails. Participants will spend approximately 20-30 minutes enrolling in the study through the study's website. During this time, they will read the consent form, answer the eligibility questions and complete the baseline questionnaire. Eligible participants are then asked if they are interested to participate in the Genetics Sub-study. Those who provide separate consent for the genetics component will complete additional questionnaires online (Between Facets and Domains Personality Test) and will be mailed a kit to provide a saliva sample. After successful completion of baseline questionnaire through the study website, eligible participants will be emailed a Letter to Doctor and a Standard Script to take to their doctor. Then, they will attend an appointment with their physician to discuss with their doctor whether the medication they have been assigned to is appropriate for them to use as smoking cessation aid. It is possible that the participant and his/her doctor will decide not to pursue smoking cessation using the assigned medication. These participants will still receive the weekly motivational emails and will be followed up at all time points, but they will not be included in the main data analysis. If the doctor believes that it is appropriate for the participants to take the assign medication, he/she will need to sign the Standard Script and fax it to the study contract pharmacy. Once the fax is received by the pharmacy, they will call the participants for a brief counseling. Then, they will fill the prescription and mail the medication to you free of charge. All participants will set a quit date of their choosing, but will start the medication 7 days prior to their target quit date. Data related to the outcome measures and adverse events will be collected at 4, 8 and 12, 26 and 52 weeks after the start of treatment in order to assess and compare both point prevalent and continuous abstinence effects of the two treatment interventions. Smoking status will be biochemically confirmed at baseline and at 26th and 52nd weeks following start of treatment using salivary cotinine measures. Medication compliance is assessed by self-report measures as part of the follow-up questionnaire. Compliance is also biochemically confirmed at 4 weeks following start of treatment.