Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, is the newest drug in the armamentarium of tobacco-addiction treatment. Improved smoking quit rates with varenicline are seen in comparison with other pharmacotherapies or behavioral treatments alone. Efficacy, tolerability and safety have been demonstrated in healthy smokers and in smokers with cardiovascular or pulmonary comorbidity, as well as in smokeless tobacco users. Varenicline is started 1 week before a target quit date, uptitrated to 1 mg twice daily, and continued for 12-24 weeks. Post-marketing reports have led to labeling changes to monitor patients for change in behavior, hostility, agitation, depressed mood and suicide-related events. Varenicline's pharmacological profile does not clearly explain an association with these adverse events. A review of placebo-controlled studies found that varenicline was not associated with self-reported neuropsychiatric symptoms, with the exception of sleep disorders. Data in smokers with psychiatric problems are limited.