Varenicline is a recently developed medication for smoking cessation, which has been available on prescription since 2006. It is a selective nicotinic acetylcholine receptor partial agonist, and is designed to reduce withdrawal symptoms and to lessen the rewards of continued smoking. Our objective in this article is to assess the efficacy of varenicline as an aid to smoking cessation and to weigh the potential benefits against the possible risks. We identified ten randomized controlled trials and one cohort study with historical controls. In total there were 7999 participants, 5112 of whom received varenicline. Eight of the trials compared varenicline with placebo for cessation, two compared it with nicotine replacement therapy and one tested extended use for relapse prevention. Three of the varenicline/placebo trials also included a bupropion arm. The recommended dosage of varenicline 1 mg twice daily more than doubled the chances of quitting at 6 months or longer, with a relative risk (RR) compared with placebo of 2.38 (95% CI 2.00, 2.84). It also outperformed bupropion (RR 1.52 [95% CI 1.22, 1.88]) and nicotine replacement (RR 1.31 [95% CI 1.01, 1.71]). A reduced dosage regimen of 1 mg daily also increased cessation (RR 1.88 [95% CI 1.35, 2.60]). In the trials, varenicline significantly reduced craving and other withdrawal symptoms. The most frequent adverse event was nausea, occurring in 30-40% of varenicline users. However, this was generally reported at mild to moderate levels, diminished over time and was associated with attributable discontinuation rates of between 0.6% and 7.6%. Other commonly occurring adverse events included insomnia, abnormal dreams and headache. Serious adverse events were rare, with no treatment-related deaths during the treatment or follow-up phases. Postmarketing surveillance has raised new questions about the safety of varenicline. In February 2008, the US FDA issued a public health advisory note, reporting a possible association between varenicline and an increased risk of behaviour change, agitation, depressed mood, and suicidal ideation and behaviour. They have required the manufacturers to revise the labelling of varenicline and the Summary of Product Characteristics, and to issue a medication guide. It is arguable that much of the reported behavioural and mood changes may be associated with nicotine withdrawal, although some effects occurred in people who continued to smoke while taking the medication. In view of the potential, if unproven, risk that varenicline may be associated with serious neuropsychiatric adverse outcomes, patients attempting to quit smoking with varenicline, and their families and caregivers, should be alerted about the need to monitor for neuropsychiatric symptoms, including changes in behaviour, agitation, depressed mood, suicidal ideation and suicidal behaviour, and to report such symptoms immediately to the patient's healthcare provider.