Inclusion Criteria:

1. Age: 25-65 years old
2. Smoking 5 or more cigarettes per day, on average, within the two months preceding the screening visit and expired CO of 6ppm or greater.
3. Able to follow verbal and written instructions in English and complete all aspects of the study
4. Provide informed consent and agree to all assessments and study procedures
5. Have an address and home telephone number where they may be reached
6. Be the only participant in their household

Exclusion Criteria:

1. Within the month immediately preceding the screening visit, use of any form of tobacco products other than cigarettes on 3 or more days within a week if the individual refuses to refrain from such tobacco use during the course of the study.
2. Within the month immediately preceding the screening visit, use of marijuana in any form on 3 or more days within a week
3. Within the two weeks immediately preceding the screening visit, involvement on more than 3 days in any formal smoking cessation activities
4. Treatment on a continuous basis within 2 weeks before the screening visit: any contraindicated medication for Varenicline or Bupropion. Classes of contraindicated medications include, but are not limited to, antiasthmatics, antipsychotics, antidepressants, antihypertensives, antiarrhythmics, antineoplastics, antiseizures, and MAO inhibitors.
5. Uncontrolled hypertension (systolic blood pressure greater than 150 or diastolic blood pressure greater than 95) or other major contraindications for Bupropion or Varenicline.
6. Severe renal impairment (Creatinine Clearance less than 30 ml/min/1.73 m2).
7. Laboratory evaluations outside normal limits and of potential clinical significance in the opinion of the investigator.
8. Meet current criteria for psychiatric disorders or substance abuse.
9. Individuals rated as moderate (6 - 9) to high (10 or greater) on suicidality as assessed by Module C of the MINI.
10. Psychiatric hospitalization within 1 year of screening date.
11. A positive urine pregnancy test during the screening period. Women who are two years post menopausal or who have had a partial or full hysterectomy will not be subject to a urine pregnancy test.
12. Pregnant, breast-feeding or of childbearing potential and is not protected by a medically acceptable, effective method of birth control while enrolled in the study.
13. Use of Varenicline or Bupropion within two weeks before the screening visit.
14. History of hypersensitivity or allergic reaction to Varenicline, tricyclic antidepressant, Bupropion (Wellbutrin, Zyban) or similar chemical classes or any component of these formulations.
15. Subject considered by the investigator as unsuitable candidate for receipt of an investigational drug, or unstable to be followed up throughout the entire duration of the study.