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 non-medical causes of agitation so that patients can receive appropriate and timely treatment. This article aims to educate all clinicians in non-medical 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. [West J Emerg Med. 2012;13(1):3–10.]