Neuronal plasticity or remodeling is most often discussed with regard to cellular and behavioral models of learning and memory. However, neuronal plasticity is a fundamental process by which the brain acquires information and makes the appropriate adaptive responses in future-related settings. Dysfunction of these fundamental processes could thereby contribute to the pathophysiology of mood disorders, and recovery could occur by induction of the appropriate plasticity or remodeling. These possibilities are supported by preclinical and clinical studies demonstrating that there are structural alterations that occur in response to stress and in patients with mood disorders. Moreover, antidepressant treatment may oppose these effects by regulation of signal transduction and gene expression pathways linked to neuronal plasticity. These findings comprise a novel conceptual framework for future studies of the etiology of mood disorders and for the development of novel therapeutic interventions.