For many patients suffering from major depressive disorder, available treatments are unsatisfactory due to long delays before the onset of effects, low response rates, poor tolerability, and high recurrence rates. Evidence now suggests that major depressive disorder is a complex syndrome fed by multiple pathways and therefore that modulating serotonergic and noradrenergic neurotransmission, while important, is insufficient. To this effect, data have shown consistently over the last 50 years that patients suffering from depression experience a wide range of circadian rhythm disturbances, and that temporary remission of symptoms can be reached with chronotherapeutic interventions. Agomelatine, a melatonergic antidepressant with an innovative pharmacological profile, is both a melatonergic receptor agonist and a 5HT(2C) receptor antagonist. Its antidepressant activity has been demonstrated in animal models and placebo-controlled trials as well as in comparator studies. Clinically and statistically significant improvements in the core symptoms of depression, as well as a rapid onset of benefits, low relapse rates upon discontinuation, and high tolerability have been noted. It is likely that the antidepressant activity of agomelatine results, at least in part, from the resynchronization of the circadian rhythms that are disturbed in many depressed patients. In a recent study, for example, treatment with agomelatine significantly improved the amplitude of the circadian rest-activity/ sleep-wake cycle and decreased depression and anxiety symptoms compared with treatment with sertraline. Together, these data suggest that agomelatine, through its innovative mechanism of action, may result in a more complete and sustained remission for chronically depressed patients.