Disuse-induced skeletal muscle atrophy occurs following chronic periods of inactivity such as those involving prolonged bed rest, trauma and microgravity environments. Deconditioning of skeletal muscle is mainly characterized by a loss of muscle mass, decreased fiber cross-sectional area, reduced force, increased fatigability and transitions in fiber types. Decreases in protein synthesis and increases in protein degradation both have been shown to contribute to muscle protein loss due to disuse, and recent work has delineated elements of both synthetic and proteolytic processes underlying muscle atrophy. This review focuses on the most recent findings related to intracellular signaling during muscle atrophy. Key findings are discussed that relate to signaling involving muscle ubiquitin ligases, FOXO activity, PGC-1α expression kinetics, and an attempt is made to construct a unifying picture of how these data can be connected to better understand disuse-induced muscle atrophy.