The inability to perform a specific normal activity suggests weakness, which can be readily distinguished from loss of stamina or endurance. Pain, cramping, and gastrointestinal complaints frequently accompany weakness. The collagen-vascular diseases and inflammatory myopathies are likely to produce myalgia and muscle tenderness. The degree of weakness is assessed for each muscle group; serial examinations can provide evidence of improvement or worsening in the condition. This chapter provides differential diagnosis for specific conditions such as cerebral hemispheric lesions, spinal cord disorders, anterior horn cell disorders, nerve root disorders, neuromuscular junction disorders, and myopathies. In the emergency department, the most serious presentation of severe muscle weakness is acute respiratory failure. The three most common primary neurological causes of acute respiratory failure are previously unrecognized amyotrophic lateral sclerosis (ALS), myasthenia gravis, and Guillain-Barré syndrome. Respiratory failure due to a neuromuscular cause is a form of restrictive pulmonary disease.