The choice of an antidepressant is tailored according to patient factors (age, sex, severity, diagnostic subtype, comorbid disorders, past response) and to drug characteristics (efficacy, tolerability, safety, simplicity of use, discontinuation syndrome).A wide range of antidepressants are available nowadays, with mode of action mainly based on the monoamine hypothesis of depression, but all have limitations: still too many nonresponding patients, late onset of action, and poor tolerability profile, resulting in low adherence. The challenges for a new antidepressant are first to provide all patients with rapid and sustained antidepressant efficacy in relieving all symptoms, second to lead patients out of depression by achieving complete remission, and third to ensure that patients are compliant throughout treatment.Agomelatine is a new antidepressant with an innovative mode of action acting as an agonist of melatonergic MT1 and MT2 receptors as well as an antagonist of serotonergic 5-HT2C receptors. These receptors play a major role in circadian rhythms, which are dysregulated in depression. Recent data suggest that the distinctive antidepressant efficacy of agomelatine results from the potential synergy between these receptors.Agomelatine rapidly improves depressive symptoms in most subtypes of depression, particularly in patients with anxiety symptoms, known as factor of resistance. Moreover, agomelatine shows greater antidepressant efficacy than fluoxetine in severely depressed patients (HAM-D total score difference over 8 weeks: 1.49; P = 0.024).Thanks to its unique impact on mechanisms at the core of depressive dysregulation, agomelatine provides doctors and patients with an innovative approach to depression treatment.