Acute agitation is a state of behavioral dyscontrol that requires intervention. Medications available in rapid delivery formats are frequently administered to treat acute agitation, either as a chemical restraint or on a voluntary basis. Prior to initiating treatment, the etiology of agitation must be evaluated. In choosing a medication, general pharmacologic principles should be followed. Medication should be selected based on the underlying cause in conjunction with weighing the risks, benefits, and side effects of medications. There are three classes of medications administered to children and adolescents to treat agitation: antihistamines, benzodiazepines, and antipsychotics. The most concerning short-term side effects of antipsychotics are their adverse neurologic effects, neuroleptic malignant syndrome, and prolonged corrected QT interval. Compared with typical antipsychotics, atypical antipsychotics have a more favorable short-term side effect profile.