Results from basic and clinical studies demonstrate that stress and depression decrease neurotrophic factor expression and neurogenesis in brain, and that antidepressant treatment blocks or reverses these effects, leading to a neurotrophic hypothesis of depression. Neurotrophic factor expression and neurogenesis are also decreased during aging and could be risk factors for depression. In contrast, exercise and enriched environment increase neurotrophic support and neurogenesis, which could contribute to the blockade of the effects of stress and aging and produce antidepressant effects. A brief overview of this work and the specific neurotrophic factors involved are discussed in this review.