Despite improvements in critical illness survival rates with recent developments in medical care, many patients still have long-term physical disabilities following stays in the intensive care unit (ICU). Critical illness-induced muscle weakness, so-called ICU-acquired weakness (ICU-AW), is a common occurrence in approximately 50% of critically ill patients in the ICU requiring mechanical ventilation for >7 days. ICU-AW contributes to increases in duration of mechanical ventilation and lengths of ICU and hospital stays and may persist among survivors for several years after discharge. Risk factors for ICU-AW include systemic inflammatory responses, severe sepsis, muscle inactivity, hyperglycemia, and use of neuromuscular blockers. Thus, the development of muscle wasting is suggested to be associated with pathophysiological alterations leading to an imbalance between muscle proteolysis and proteosynthesis through several cellular signaling networks. This chapter presents a review of the literature regarding critical illness-induced muscle wasting and describes potential treatment of excessive muscle catabolism.