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Major depressive disorder (MDD) is characterized by structural and neurochemical changes in limbic structures, including the hippocampus, that regulate mood and cognitive functions. Hippocampal atrophy is observed in patients with depression and this effect is blocked or reversed by antidepressant treatments. Brain-derived neurotrophic factor and other neurotrophic/growth factors are decreased in postmortem hippocampal tissue from suicide victims, which suggests that altered trophic support could contribute to the pathophysiology of MDD. Preclinical studies demonstrate that exposure to stress leads to atrophy and cell loss in the hippocampus as well as decreased expression of neurotrophic/growth factors, and that antidepressant administration reverses or blocks the effects of stress. Accumulating evidence suggests that altered neurogenesis in the adult hippocampus mediates the action of antidepressants. Chronic antidepressant administration upregulates neurogenesis in the adult hippocampus and this cellular response is required for the effects of antidepressants in certain animal models of depression. Here, we review cellular (e.g. adult neurogenesis) and behavioral studies that support the neurotrophic/neurogenic hypothesis of depression and antidepressant action. Aberrant regulation of neuronal plasticity, including neurogenesis, in the hippocampus and other limbic nuclei may result in maladaptive changes in neural networks that underlie the pathophysiology of MDD.