Muscle contraction results in generation of reactive oxygen and nitrogen species (RONS) at a rate determined by the intensity, frequency, and duration of the exercise protocols. Strenuous exercise causes oxidation of protein, lipid, and DNA, release of cytosolic enzymes, and other signs of cell damage; however, only exhaustive exercise is detrimental. Indeed, the regulation of vascular tone, the excitation-contraction coupling, growth, and differentiation in skeletal muscle, are governed in part by RONS. This is accomplished by RONS interaction with redox-sensitive transcription factors, leading to increased gene expression of antioxidant enzymes, cytoprotective proteins, and other enzymes involved in muscle metabolic functions. However, high levels of RONS generation are known to cause oxidative stress, activate certain pathogenic pathways, and accelerate aging. This article reviews research from the past decades on the interplay of oxidants and antioxidants in skeletal muscle, with particular reference to increased contractile activity. Adaptation of muscle to increased oxidative stress and the potential mechanisms involved will be highlighted. The role of redox-controlled cell signaling in skeletal muscle health and function is also described.