Preclinical and clinical studies have demonstrated that stress or depression can lead to atrophy and cell loss in limbic brain structures that are critically involved in depression, including the hippocampus. Studies in experimental animals demonstrate that decreased birth of new neurons in adult hippocampus could contribute to this atrophy. In contrast, antidepressant treatment increases neurogenesis in the hippocampus of adult animals and blocks the effects of stress. Moreover, blockade of hippocampal neurogenesis blocks the actions of antidepressants in behavioral models of depression, demonstrating a direct link between behavior and new cell birth. This perspective reviews the literature in support of the hypothesis that altered birth of new neurons in the adult brain contributes to the etiology and treatment of depression and considers research strategies to test this hypothesis.