Violent behavior associated with mental disorders is a common reason for admission to a psychiatric inpatient unit. Once hospitalized, patients may continue to be intermittently agitated and have persistent aggressive behaviors, preventing their discharge back into the community. Managing agitation quickly with effective pharmacological agents can avoid further escalation to aggression and violence. In the acute setting, this usually involves the parenteral use of antipsychotics, with or without benzodiazepines. Within the past decade, short-acting intramuscular formulations of second-generation antipsychotics have become available and provide a means to induce calm with a substantially lower risk of acute dystonia or akathisia compared with haloperidol. New alternative formulations that avoid injections include inhalation and sublingual administration. Longer-term management of persistent aggressive behavior by reducing the frequency and intensity of future episodes of agitation is more complex. In contrast to agitation associated with schizophrenia or bipolar mania, no agents have yet been approved by regulatory agencies for the treatment of persistent aggressive behavior. The strongest evidence supports the use of clozapine as an antihostility agent, followed by olanzapine. Adjunctive strategies with anticonvulsants and beta-adrenergic agents may also be worthwhile to consider.