Basic and clinical studies over the past 10 years have lead to a fundamental shift in our understanding of mood disorders. These studies demonstrate that mood disorders and stress are accompanied by structural alterations in the brain; moreover, these structural alterations are reversible with antidepressant treatment. These alterations include changes in the length and number of neuronal processes, the number of neurons and glia, and even the rate of neurogenesis in the adult brain. Work is also being conducted to identify the molecular mechanisms underlying these changes and the adaptations that are critical to the therapeutic actions of antidepressant treatment. Some of the intracellular targets include second messengers, gene transcription factors, and neurotrophic factors that could oppose the actions of stress and depression. Taken together, this exciting new work describes and details structural alterations of limbic brain regions that are extremely dynamic and adaptive. Further understanding of the abnormalities in these systems that lead to mood disorders will provide more efficacious and possibly faster-acting therapeutic interventions.