Numerous medical and psychiatric conditions can cause agitation; some of these causes are life threatening. It is important to be able to differentiate between medical and nonmedical causes of agitation so that patients can receive appropriate and timely treatment. This article aims to educate all clinicians in nonmedical settings, such as mental health clinics, and medical settings on the differing levels of severity in agitation, basic triage, use of de-escalation, and factors, symptoms, and signs in determining whether a medical etiology is likely. Lastly, this article focuses on the medical workup of agitation when a medical etiology is suspected or when etiology is unclear.