Maintaining leanness and a physically active lifestyle during adulthood reduces systemic inflammation, an underlying factor in multiple chronic diseases. The anti-inflammatory influence of near-daily physical activity in lowering C-reactive protein, total blood leukocytes, interleukin-6, and other inflammatory cytokines may play a key role in lowering risk of cardiovascular disease, certain types of cancer, type 2 diabetes, sarcopenia, and dementia. Moderate exercise training causes favorable perturbations in immunity and a reduction in incidence of upper respiratory tract infection (URTI). During each bout of moderate exercise, an enhanced recirculation of immunoglobulins, neutrophils, and natural killer cells occurs that persists for up to 3-h post-exercise. This exercise-induced surge in immune cells from the innate immune system is transient but improves overall surveillance against pathogens. As moderate exercise continues on a near-daily basis for 12–15 weeks, the number of symptoms days with URTI is decreased 25%–50% compared to randomized sedentary controls. Epidemiologic and animal studies support this inverse relationship between URTI risk and increased physical activity.