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Major depressive disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Despite its considerable burden, our understanding of its pathophysiology remains rudimentary, and a validated biomarker has yet to be identified. Antidepressants are the most common treatment for MDD, yet roughly one-third of patients experience an inadequate response. Thus, there is a great need for not only identifying biomarkers of MDD but also those that can predict and monitor or just monitor response to treatment.MicroRNAs (miRNAs) act as endogenous fine-tuners and on–off switches of gene expression. Several lines of evidence now suggest that miRNAs are involved in the pathogenesis of neuropsychiatric disorders. As such, miRNAs offer great hope as biomarkers of disease and response to treatment.In this review, we discuss the growing field, investigating peripheral miRNAs as potential biomarkers of major depression and treatment response. A noninvasive and validated biomarker of MDD or treatment response will help clinicians guide treatment selection. Ultimately, these findings provide important steps in the development of early diagnostic tools, preventive strategies, and effective pharmacological treatment for psychiatric disorders.