Agomelatine (AGM) was approved for the treatment of major depressive disorder (MDD) in adults by the European Medicines Agency (EMA) in February 2009. It is an analogue of melatonin and features a unique pharmacodynamic profile with agonism on both types of melatonergic receptors (MT1/MT2) and antagonism at serotonergic 5-HT2C receptors. There is, however, an ongoing debate regarding the efficacy and safety of this novel antidepressant agent, originally evoked by claims of a significant publication bias underlying the assessment of AGM being an effective antidepressant. Indeed, two recent comprehensive metaanalyses of published and unpublished clinical trials found evidence for a relevant publication bias. However, due to its statistically significant advantage over placebo based on the results of these metaanalyses AGM must be referred to as an effective antidepressant agent in the acute phase of MDD. However, the effect sizes of AGM in the treatment of MDD were evaluated as being small in comparison to other antidepressant agents. In addition, there is insufficient evidence for the efficacy of AGM in relapse prevention of MDD. Apart from efficacy issues, AGM appears to have the potential to exhibit severe hepatotoxicity (the EMA has identified AGM-associated “hepatotoxic reactions” as a new safety concern in September 2013) that is currently poorly understood. Considering these aspects, it seems inappropriate to evaluate AGM as an antidepressant agent of first choice. Nevertheless, its unique mechanism of action with particular sleep modulating effects may represent a specific treatment strategy for patients with particular characteristics; further studies with thorough characterization of patients are needed to test this hypothesis.