Skeletal muscle fibers are malleable and undergo rapid remodeling in response to increased contractile activity (i.e., exercise) or prolonged periods of muscle inactivity (e.g., prolonged bedrest). Exploration of the cell signaling pathways regulating these skeletal muscle adaptations reveal that redox signaling pathways play a key role in the control of muscle remodeling during both exercise and prolonged muscle inactivity. In this regard, muscular exercise results in an acute increase in the production of reactive oxygen species (ROS) in the contracting fibers; however, this contraction-induced rise in ROS production rapidly declines when contractions cease. In contrast, prolonged muscle disuse results in a chronic elevation in ROS production within the inactive fibers. This difference in the temporal pattern of ROS production in muscle during exercise and muscle inactivity stimulates divergent cell-signaling pathways that activate both genomic and nongenomic mechanisms to promote muscle remodeling. This review examines the role that redox signaling plays in skeletal muscle adaptation in response to both prolonged muscle inactivity and endurance exercise training. We begin with a summary of the sites of ROS production in muscle fibers followed by a review of the cellular antioxidants that are responsible for regulation of ROS levels in the cell. We then discuss the specific redox-sensitive signaling pathways that promote skeletal muscle adaptation in response to both prolonged muscle inactivity and exercise. To stimulate future research, we close with a discussion of unanswered questions in this exciting field.