Acute non-traumatic weakness may be life threatening if it involves the respiratory muscles or is associated with autonomic dysfunction. Most patients presenting with acute muscle weakness have a worsening neurological disorder that requires a rapid, systematic evaluation, and detailed neurological exam to localize the disorder. Urgent laboratory tests and neuroimaging are needed in many patients to make the diagnosis. Because acute weakness is a common presenting sign of neurological emergencies, it was chosen as an Emergency Neurological Life Support protocol. Causes of acute non-traumatic weakness are discussed by both presenting clinical signs and anatomical location. For each diagnosis, key features of the history, examination, investigations, and treatment are outlined in the included tables.