Objective: To present an updated, comprehensive review on clinical and pre-clinical studies on agomelatine. Method: A MEDLINE, Psycinfo and Web of Science search (1966-May 2009) was performed using the following keywords: agomelatine, melatonin, S20098, efficacy, safety, adverse effect, pharmacokinetic, pharmacodynamic, major depressive disorder, bipolar disorder, Seasonal Affective Disorder (SAD), Alzheimer, ADHD, Generalized Anxiety Disorder (GAD), Panic Disorder (PD), Obsessive-Compulsive Disorder (OCD), anxiety disorders and mood disorder. Study collection and data extraction: All articles in English identified by the data sources were evaluated. Randomized, controlled clinical trials involving humans were prioritized in the review. The physiological bases of melatonergic transmission were also examined to deepen the clinical comprehension of agomelatine melatonergic modulation. Data synthesis: Agomelatine, a melatonergic analogue drug acting as MT1/MT2 agonist and 5-HT2C antagonist, has been reported to be an effective antidepressant therapy. Conclusions: Although a bias in properly assessing the “sleep core” of depression may still exist with current screening instruments, therefore making difficult to compare agomelatine efficacy to other antidepressant ones, comparative studies showed agomelatine to be an intriguing option for depression and, potentially, for other therapeutic targets as well.