Acute non-traumatic weakness may be life-threatening if it involves respiratory muscles or is associated with dysautonomia. Most patients presenting with an acute muscle weakness have a worsening neurologic disorder that requires a rapid, systematic approach, and detailed neurologic localization of the findings. In many patients, urgent laboratory tests are needed and may involve neuroimaging. Because acute weakness is a common presenting sign of neurological emergencies, it was chosen as an Emergency Neurological Life Support protocol. An inclusive list of causes of acute weakness is explored, both by presenting complaint and anatomical location, with an outline of the key features of the history, examination, investigations, and treatment for each diagnosis.