Basic research in rodents has demonstrated that exposure to stress decreases levels of brain-derived neurotrophic factor (BDNF) in brain regions associated with depression. In contrast, antidepressant treatment produces the opposite effect and blocks the effects of stress on BDNF. BDNF upregulation and possibly other neurotrophic/growth factors could reverse or block the atrophy and cell loss that has been observed in rodent stress models and in depressed patients. The morphological alterations observed in depressed patients could result from decreased size or number of glia and/or neurons and may include regulation of adult neurogenesis. This article reviews the primary work leading to a neurotrophic hypothesis of depression and antidepressant action and the cellular mechanisms and signal transduction pathways that underlie these effects.