Muscle is a dynamic, plastic, and malleable tissue that is highly sensitive to mechanical and metabolic signals. Muscle mass is regulated by protein homeostasis, with protein being continually turned over, reflecting a balance between synthesis and breakdown. This chapter discusses the effect of critical illness on skeletal muscle mass, protein homeostasis, and the intracellular signalling driving anabolism and catabolism. The focus will be on the unique challenges to which the skeletal muscle are exposed, such as inflammation, sepsis, sedation, and inadequate nutrition, which, in combination with the disuse signals of immobilization and bed rest, engender dramatic changes in muscle structure and function. The mechanisms regulating muscle loss during critical illness are being unravelled, but many questions remain unanswered. Detailed understanding of these mechanisms will help drive strategies to minimize or prevent intensive care-acquired muscle weakness and the long-term consequences experienced by ICU survivors.