Physical activity is emerging as one of the most promising non-pharmaceutical treatments for depression. Greater amounts of self-reported physical activity are associated with fewer depressive symptoms in epidemiological studies and randomized interventions find that participation in physical activity enhances mood in depressed populations. A Cochrane review of 32 randomized interventions concluded that participation in physical activity is effective for reducing depressive symptoms compared to either no treatment or to a control condition. Importantly, antidepressants and physical activity may work through similar biological pathways to influence both mood and cognitive function. In fact, both antidepressants and physical activity increase levels of Brain-derived neurotrophic factor (BDNF) in serum and hippocampus, may mitigate or reverse hippocampal atrophy, influence expression and kinetics of serotonin and GABA pathways, regulate brain network connectivity, alter inflammatory pathways, and improve sleep efficiency. Our proposal aims to characterize these effects from the genetic to the behavioral and cognitive level, and isolate the effects of physical activity from those of medication.