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This systematic review identified published studies that evaluated the use of pro re nata (PRN) medication in patients with acute agitation or aggression of undifferentiated etiology.A literature search was conducted of PubMed and MEDLINE for randomized controlled trials (RCTs) that evaluated the use of PRN medications for individuals with undifferentiated agitation or aggression. Bibliographic databases of published articles were also searched for additional studies.A total of 15 studies were identified that assessed the effects of first-generation antipsychotics (FGAs), second-generation antipsychotics (SGAs), benzodiazepines, and combination therapies. All RCTs showed variable degrees of sedation and decreased agitation over time with the use of these medications, as well as variable levels of adverse events.Evidence exists to support the use of specific SGAs as first-line PRN medications in the management of acutely agitated individuals. While evidence exists to support the use of FGAs, benzodiazepines, and combination therapy, efficacy is similar for each class, and SGAs appear to have the most favorable adverse effect profile.