Varenicline, a partial agonist of α4β2 nicotinic acetylcholine receptors, is the most recently approved drug for smoking cessation. This paper reviews the outcomes of Phase 2 and Phase 3 clinical trials that assess the efficacy of varenicline in comparison to placebo and other smoking cessation pharmacotherapies, ie, sustained-release bupropion (bupropion SR) and nicotine transdermal patch. Varenicline has higher abstinence rates than placebo and the alternative active treatments at the end of standard regimen treatment periods. Significantly higher abstinence rates were also found with varenicline in comparison to both placebo and bupropion SR at the end of a 40-week non-treatment follow-up period. Varenicline typically tripled the abstinence rates compared with placebo. In addition, varenicline reduced craving and withdrawal symptoms as well as some of the positive experiences associated with smoking to a greater extent than placebo, bupropion SR, and nicotine replacement therapy (NRT). These findings are consistent with the proposed agonist/antagonist effects of varenicline. Preliminary studies assessing individual variables such as smoking dependency level and smoking reinforcement types provide justification to examine further the effects of varenicline according to these individual factors. Outcomes from such research could improve our understanding of varenicline’s mechanism of action and could ultimately help clinicians to develop individualized smoking cessation programs. Also, given varenicline’s ability to reduce the reward from smoking, it might be helpful to use it before cessation to motivate or prepare smokers for a quit attempt.