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It is becoming increasingly clear that physical activity in children plays a critical role in growth and development, therapy for certain chronic diseases and disabilities, and in the pediatric origins of a variety of bone, metabolic, and cardiovascular diseases. New mechanistic insights have created the opportunity for a phase shift in understanding of the links between exercise and health in the context of the growing child.Exercise even in healthy children profoundly alters stress, immune, and inflammatory mediators including peripheral blood mononuclear cells and circulating pro- and anti-inflammatory cytokines (like interleukin-6). Moreover, exercise even in healthy adults stimulates the production of reactive oxygen species (ROS) and mediators that attenuate them. Oxidative stress, in turn, alters growth and stress mediators. Both ROS and stress/inflammatory factors interact with powerful growth mediators like growth hormone and insulinlike growth factor-I. These findings suggest specific ways in which the balance between pro- and anti-inflammatory, catabolic, and anabolic factors associated with exercise can influence health and growth in children.To address the current epidemic of physical inactivity and obesity in children and to optimize the therapeutic effects of exercise in children with disease and disability will require real changes in environments (eg, schools and playgrounds); innovative approaches to rehabilitation of children with chronic disease and disability; and enlightened training of child health professionals. Identifying novel exercise mechanisms involving stress, inflammation, and growth factors will help guide these efforts.