© 2015 by Nova Science Publishers, Inc. All rights reserved. Major depressive disorder (MDD) is a major public health concern. Although much work has been done to characterize MDD, a large number of MDD patients do not respond to the currently available medications and the relapse rate for depression is quite high. Thus, there is an urgent need to fully understand the neurobiological abnormalities associated with MDD and develop target-based therapeutic approaches. In this context, microRNAs (miRNAs) have emerged as important gene regulators which are involved in many higher brain functions. Because miRNAs show a highly regulated expression, they contribute in the development and maintenance of a specific transcriptome and thus have the unique ability to influence a wide range of physiological and disease phenotypes. Recent studies demonstrating involvement of miRNAs in several aspects of neural plasticity, stress response, and more direct studies in human postmortem brain, peripheral blood cells - provide strong evidence that miRNAs can not only play a critical role in MDD pathogenesis but can also open novel avenues for the development of therapeutic targets. In this chapter, these aspects are discussed in a comprehensive manner.