Oxidative stress has been shown to play a role in the etiology of several chronic diseases, including cardiovascular disease, diabetes mellitus, and cancer. Free radicals and, most prominently, the superoxide radical, result from oxidative metabolism and several enzyme-catalyzed reactions, and endogenous cellular antioxidants dismutate many reactive oxygen species (ROS). Under certain conditions, ROS production can outpace dismutation (e.g., long-term sedentariness and positive energy balance) and the result is oxidative stress, with proteins, lipids, and DNA the most common targets of radicals. However, the molecules that contribute to oxidative stress also appear to participate in vital cell signaling activity that supports health and stimulates favorable adaptations to exercise training, such that inhibiting ROS formation prevents common adaptations to training. Furthermore, researchers have recently suggested that some proteins are not as readily formed when the redox state of the cell is insufficiently oxidative. Exercise training appears to optimize the redox environment by dramatically enhancing the capacity of the cell to neutralize ROS while regularly creating oxidative environments in which membrane and secretory proteins can be synthesized. The role that exercise plays in enhancing management of ROS likely explains many of the associated health benefits.