With an estimated life-time prevalence of 15 to 17% and an incapacitating illness in 50% of cases, depressive spectrum disorders represent a heavy public health burden. Despite considerable efforts to underpin the molecular and cellular changes associated with depressive states, a global understanding of the pathophysiology of major depressive disorders (MDD) is still lacking. It is now acknowledged that deficits in synaptic plasticity, such as those resulting from chronic stress, can set the stage for the onset of depression. As a corollary, antidepressants balance neurotransmitter systems and help restore neuronal activity. In recent years, microRNAs have emerged as key protagonists in numerous physiopathological conditions including CNS function and disease. This review summarizes the current evidence for an involvement of microRNAs in the pathophysiology of depression and their contribution to the action of antidepressants.