Agomelatine is an antidepressant drug that is a synthetic analogue of the hormone melatonin. It stimulates the activity of melatonin MT(1) and MT(2) receptors and inhibits the activity of serotonin 5HT(2C) receptor subtypes. The objective of this article is to critically review and evaluate the benefits and risks of agomelatine for the treatment of major depression. The published literature through April 2011 for articles relating to agomelatine, together with unpublished data on agomelatine available from the European Medicines Agency, the US FDA, US ClinicalTrials.gov and the Novartis Clinical Trial Results Database are reviewed. The antidepressant efficacy of agomelatine has been systematically assessed in ten short-term, placebo-controlled studies and three longer-term, placebo-controlled, relapse prevention studies. Five short-term trials demonstrated clinically modest, but statistically significant, benefits over placebo, although two of these studies reported opposite effects for 25 mg versus 50 mg doses. The other five short-term trials did not find agomelatine more effective than placebo, but in two of these studies the active control drug was more effective than placebo. A meta-analysis of six European trials demonstrated a small, statistically significant, marginally clinically relevant difference in efficacy favouring agomelatine over placebo. The only placebo-controlled study in elderly patients did not demonstrate a significant benefit for agomelatine. Agomelatine was shown to be more effective than placebo in one of three relapse prevention studies. Agomelatine was generally well tolerated compared with placebo. Its adverse effect profile is different to that of other antidepressant drugs, but its overall tolerability in studies with other antidepressants as active control drugs did not appear to be substantially better than the controls. Agomelatine is contraindicated in patients with impaired liver function and in patients taking drugs that potently inhibit cytochrome P450 1A2 metabolic enzymes. Because elevated liver enzymes are common, and there is a rare risk of more serious liver reactions, routine laboratory monitoring of liver function is recommended periodically throughout treatment. Based on this comprehensive review, agomelatine does not have clinically significant advantages compared with other antidepressant drugs, and it has certain limitations and disadvantages. Because of the unique pharmacology of agomelatine and its reported tolerability profile, it should only be considered as an alternative drug for patients who do not respond to or cannot tolerate other antidepressant drugs.