MicroRNAs are important regulators of gene expression and associated with stress-related psychiatric disorders. Here, we report that exposing mice to chronic stress led to a specific increase in microRNA-15a levels in the amygdala-Ago2 complex and a concomitant reduction in the levels of its predicted target, FKBP51, which is implicated in stress-related psychiatric disorders. Reciprocally, mice expressing reduced levels of amygdalar microRNA-15a following exposure to chronic stress exhibited increased anxiety-like behaviors. In humans, pharmacological activation of the glucocorticoid receptor, as well as exposure to childhood trauma, was associated with increased microRNA-15a levels in peripheral blood. Taken together, our results support an important role for microRNA-15a in stress adaptation and the pathogenesis of stress-related psychopathologies.