Major affective disorders are common and disabling conditions associated with significant psychosocial impairment and suicidal risk in the general population. At least 3-4% of all depressive individuals die by suicide. At a molecular level, affective disorders and suicidal behaviour have been recently associated with abnormalities in structural and synaptic plasticity. A recent hypothesis suggested that small non-coding RNAs (ncRNAs), in particular microRNAs (miRNAs), play a critical role in the translational regulation at the synapse. Here we summarized the current literature on miRNAs putative subcellular localization and sites of action in mature neurons analyzing their role in neurogenesis, synaptic plasticity, pathological stress changes, major affective disorders and suicidal behaviour. miRNAs have played a fundamental role in the evolution of brain functions. The perturbation of some intracellular mechanisms as well as impaired assembly, localization, and translational regulation of specific RNA binding proteins may affect learning and memory, presumably contributing to the pathogenesis of major affective disorders and perhaps suicidal behaviour. Also, miRNA dys-regulation has also been associated with several neuropsychiatric diseases. However, further evidence are needed in order to directly clarify the role of miRNAs in major affective disorders and suicidal behaviour [Abstract words (189); keywords (4): microRNAs; synaptic plasticity; major affective disorders; suicidal behaviour]. © 2013 Nova Science Publishers, Inc. All rights reserved.