One of the ongoing clinical challenges associated with the management of major depressive disorder is the fact that many patients do not achieve complete remission and even fewer patients remain in remission. Residual symptoms and poor treatment adherence are two of the main risk factors for relapse with current therapies. In order to face these challenges, clinicians need new treatment strategies that can provide more sustained, longer-term efficacy and adherence. Agomelatine, an innovative antidepressant, is a melatonergic MT(1)/MT(2) agonist with 5HT(2C) receptor antagonist activity. Randomized, controlled studies have shown that agomelatine reduces depression symptoms and is well tolerated during short-term and long-term treatment strategies. Low relapse rates (21.7% for agomelatine versus 46.6% for placebo after 6 months of continuation treatment; p < 0.0001) have been reported and are believed to be the result of the cumulative effect of agomelatine at all stages of depression. In particular, specific residual symptoms, such as anxiety and sleep disturbances, which increase the rate of relapse, are significantly improved with agomelatine treatment. Furthermore, quality of life during remission, which can affect adherence rates, is likely to be improved because sexual function and weight are preserved. The combination of these unique properties suggests that treatment with agomelatine will provide more sustained, longer-term remission because antidepressant efficacy is combined with fewer residual symptoms and better tolerability and adherence.