ICU-acquired weakness (ICUAW) occurs with reported incidence rates from 25% to 100%. Risk factors include immobility, sepsis, persistent systemic inflammation, multiorgan system failure, hyperglycemia, glucocorticoids, and neuromuscular blocking agents. The pathophysiology remains unknown. Clinical features may be neuropathic, myopathic, or a combination of both. Although manual muscle testing is more practical in diagnosing ICUAW, the “gold standard” for the diagnosis of ICUAW remains electromyography and nerve conduction studies. The only potential interventions known to date to prevent ICUAW include insulin therapy and early rehabilitation, but patients still may develop activity limitations in the acute care hospital. For these patients, rehabilitation may continue in long-term care hospitals, inpatient rehabilitation facilities, or skilled nursing facilities. ICUAW is a catastrophic and debilitating condition that potentially leaves patients with permanent residual activity limitations and participation restrictions. Further research on ICUAW needs to better understand its pathophysiology so that more definitive preventive and therapeutic interventions may be developed.