The intimate relationship between depressive disorders and biological rhythm disturbances has long been known. One major component in diurnal rhythm regulation in mammals, like humans, is the melatonin axis and its close connections with serotonergic and noradrenergic structures. In major depression various functional anomalies have been shown in all of these systems. Agomelatine is a novel antidepressant with direct agonist activity at the melatonin MT1 and MT2 receptors, and a selective antagonist action at the serotonin 5HT2C receptor. It has no measurable affinity to any other known receptor. In animal models agomelatine has antidepressant-like and anxiolytic-like properties, it promotes sleep, and is able to resynchronize various experimentally uncoupled or phase-shifted biological rhythms. In randomized and controlled clinical trials agomelatine appears to be an effective antidepressant, comparable to standard SSRI/SNRI drugs, with excellent safety and tolerability profile. It usually produces mild and transient side effects, similar to those seen in patients receiving placebo. Sleep architecture and subjective measures of sleep quality may also respond favorably. Agomelatine causes significantly less sexual dysfunction than a reference SNRI. No discontinuation symptoms have been observed upon abrupt withdrawal. The overall dropout rates in the clinical trials have been remarkably low, suggesting good acceptability and compliance. Even though most current antidepressants are effective, they also have weaknesses; therefore we still need innovative drugs with novel biochemical actions, faster efficacy and/or better tolerability.