Major depression is a debilitating disease. Despite a tremendous amount of research, the molecular mechanisms associated with the etiopathology of major depression are not clearly understood. Several lines of evidence indicate that depression is associated with altered neuronal and structural plasticity and neurogenesis. MicroRNAs are a newly discovered prominent class of gene expression regulators that have critical roles in neural development, are needed for survival and optimal health of postmitotic neurons, and regulate synaptic functions, particularly by regulating protein synthesis in dendritic spines. In addition, microRNAs (miRNAs) regulate both embryonic and adult neurogenesis. Given that miRNAs are involved in neural plasticity and neurogenesis, the concept that miRNAs may play an important role in psychiatric illnesses, including major depression, is rapidly advancing. Emerging evidence demonstrates that the expression of miRNAs is altered during stress, in the brain of behaviorally depressed animals, and in human postmortem brain of depressed subjects. In this review article, the possibility that dysregulation of miRNAs and/or altered miRNA response may contribute to the etiology and pathophysiology of depressive disorder is discussed. © 2011 Elsevier B.V.