Cigarette smoking is the leading preventable cause of death. Varenicline is a partial agonist at nicotinic alpha(4)beta(2) receptors being tested for smoking cessation. During a trial in which the drugs were administered for 12 weeks, the continuous abstinence rate was 17.7% in the placebo group, which improved to 29.5% with bupropion SIR and to 44.0% with varenicline 1 mg b.i.d. Abstinence rates for weeks 9 through 52 were 8.4, 16.1 and 21.9% for placebo, bupropion and varenicline, respectively. Prolonging the treatment with varenicline may give better quit rates. In this trial, after 12 weeks of open-label varenicline, the abstainers received either another 12 weeks of varenicline or placebo. At week 24, more of the participants in the varenicline group (70.5%) were abstinent than in the placebo group (49.6%). The most common adverse effect in both these trials with varenicline was nausea. This prompted a trial comparing the efficacy and safety of four varenicline dosing regimens, to determine whether a lower dose was effective and with reduced adverse effects. After 52 weeks, the abstinence rates were 3.9% in the placebo group, and higher in the varenicline 0.5 mg b.i.d. (18.5%) and 1 mg b.i.d. groups (22.4%). The rates of nausea were not significantly increased by varenicline 0.5 mg b.i.d., but were by varenicline 1 mg b.i.d. in summary, varenicline may give slightly higher smoking cessation rates than bupropion, but the smoking cessation rates, especially at 52 weeks, remain low.