Skeletal muscle atrophy can result from prolonged periods of skeletal muscle inactivity due to bed rest, denervation, or unloading. Such unloading-associated atrophy of skeletal muscle is characterized by both an increase in protein degradation and a decrease in protein synthesis. Successful treatments for skeletal muscle atrophy could either block protein degradation pathways activated during atrophy, or stimulate protein synthesis pathways induced during skeletal muscle hypertrophy. In this review, we mainly focus on the Insulin-like growth factor 1 (IGF-1)/Insulin receptor substrate 1 (IRS-1) pathway in muscle, because there is increasing evidence indicating that inhibition of this pathway in muscle is involved in the progression of disuse atrophy. We also focus on the signaling pathways that control skeletal muscle atrophy, including muscle atrophy-associated ubiqitin ligases such as Cbl-b, muscle RING finger 1 (MuRF1), and muscle atrophy F-box (MAFbx)/atrogin-1.