Excited delirium syndrome (ExDS) is a specific type of extreme agitation. As patients with ExDS are often transported to an emergency department (ED), they are also cared for by emergency medicine clinicians. Currently, the majority of reported cases of ExDS are associated with stimulant drug use, such as cocaine or methamphetamine, although cases of ExDS still occur in psychiatric patients who are untreated or have abruptly discontinued their medication. This chapter reviews the existing literature on evaluation and treatment considerations for ExDS. Expert consensus guidelines recognize three classes of medications for initial calming of agitated patients: benzodiazepines, first-generation antipsychotics (FGA), and second-generation antipsychotics (SGA). Attention to airway maintenance, breathing adequacy, and volume resuscitation, along with rapid treatment of hypoglycemia, hyperthermia, and metabolic acidosis may be life saving. ExDS is a medical emergency, and cooperative protocols are needed between law enforcement, EMS, and local emergency departments to best manage these patients.