Prolonged periods of skeletal muscle inactivity due to bed rest, denervation, hindlimb unloading, immobilization, or microgravity can result in significant muscle atrophy. The muscle atrophy is characterized as decreased muscle fiber cross-sectional area and protein content, reduced force, increased insulin resistance as well as a slow to fast fiber type transition. The decreases in protein synthesis and increases in protein degradation rates account for the majority of the rapid loss of muscle protein due to disuse. However, we are just beginning to pay more attention on the identification of genes involved in triggering initial responses to physical inactivity/microgravity. Our review mainly focuses on the signaling pathways involved in protein loss during disuse atrophy, including two recently identified ubiquitin ligases: muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx). Recent reports suggest that inhibition of the IGF-1/PI3K/Akt pathway in muscle may be involved in the progression of disuse atrophy. NF-kappaB seems to be a key intracellular signal transducer in disuse atrophy. Factors such as myostatin, p38 and calcineurin can induce muscle protein loss under specified conditions, but further experiments are needed to determine whether they are necessary components of disuse atrophy. Where possible, the molecular mechanisms underlying the slow to fast fiber type transition and increased insulin resistance in atrophic muscles are discussed as well. Collectively, the disuse-induced muscle atrophy is a highly ordered process that is controlled by interactions between intracellular signaling pathways rather than isolated pathways.