Acutely agitated and combative patients are commonly seen and evaluated by health care providers in the emergency department. Treatment options have evolved significantly in recent years with the advent of intramuscular atypical antipsychotics and an expanded repertoire of patient-friendly oral formulations. Selection of the ideal pharmacologic treatment of an acutely agitated patient strengthens the patient–prescriber relationship and promotes adherence to future therapy. In this article, advantages and disadvantages of various treatment modalities for undifferentiated, psychotic, and nonpsychotic agitation are reviewed, including alternatives to the commonly prescribed haloperidol and lorazepam combination. Atypical antipsychotics may be superior in certain patients, with the added benefit of easier conversion to maintenance therapy. Special consideration is given to the treatment of acutely agitated geriatric patients suffering from delirium and/or dementia. Management of these patients should be guided by etiology and patient characteristics to obtain maximum therapeutic benefit. Although emergency department providers may only see a given patient once, the health care team must have an evidence-based approach to the care that is provided in the emergency department, as it can significantly influence the patient's overall course of treatment in the outpatient setting.