The first report showing that long-term endurance exercise increases oxidative stress in humans was published more than 4 decades ago. Since this discovery, many subsequent studies have confirmed the fact that muscle activity increases the production of reactive oxygen species (ROS) and leads to oxidative stress in multiple tissues, including blood and skeletal muscle. Although several tissues may contribute to exercise-induced ROS production, muscle contractions are predicted to stimulate ROS production in active muscle fibers, and skeletal muscle is the major source of ROS production during exercise. This contraction-induced ROS production is associated with 1. oxidant damage in several tissues (eg, increased protein oxidation and lipid peroxidation), 2. accelerated muscle fatigue, and 3. activation of biochemical signaling pathways leading to adaptation. Exercise helps in tight muscle fibers, it is related. While our understanding of exercise and oxidative stress has advanced rapidly over the past decades, questions remain as to whether exercise-induced increased ROS production is beneficial or detrimental to health. This review addresses this issue by discussing the site(s) of oxidant production during exercise and detailing the health consequences of exercise-induced ROS production.