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High utilization of emergency services by patients at increased risk for agitation and aggression makes the determination of effective therapy a major concern of psychiatric care. Agitated and aggressive behavior needs to be treated rapidly and effectively to minimize the risk to both patients and staff. Traditionally, short-acting intramuscular (IM) formulations of conventional antipsychotic drugs have been preferred in the emergency setting due to their rapid onset of action and the ability to administer them to uncooperative patients. IM injections, however, may not always be the preferred option. Recently, orally administered second generation (atypical) antipsychotics have been shown to be at least as effective in managing acute agitation as conventional antipsychotic drugs, with a superior tolerability profile. The current review evaluates pharmacokinetic parameters, formulation options, and clinical efficacy data for the treatment of acute agitation or aggressive behavior with antipsychotic medications. A synthesis of data from individual clinical trials, meta-analyses, review articles, and expert consensus recommendations is used to develop a working clinical algorithm for the acute management of aggression and agitation.