Regular physical activity and especially aerobic exercise are associated with reduced risk of disease and enhanced longevity, but the molecular mechanisms of these health benefits remain obscure. A comprehensive metabolomic approach was used to characterize the changes in blood levels of >200 metabolites upon vigorous exercise and identified two dozen that changed substantially. One, niacinamide, is intimately related to the metabolism of nicotinamide adenine dinucleotide (NAD(+)) and its reduced form NADH, which is in turn linked with exercise capacity as well as health status. Intensive investigation of metabolic changes with exercise could lead to pharmacological attempts to mimic the beneficial effects of exercise, an approach we term "gymnomimetics."