Weakness has a broad differential diagnosis. A paradigm for organizing possibilities is to consider what part of the nervous system is involved, ranging from brain, spinal cord, nerve roots, and peripheral nerves to the neuromuscular junction. The clinician can consider internal versus external causes. Some neurologic conditions have subtle presentations yet carry a risk of short-term decompensation if not recognized. It is helpful to consider whether an emergency department presentation of weakness is a new disease process or represents an exacerbation of an established condition. Emergency presentations of weakness are challenging, and one must carefully consider potential serious causes.