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Agitation is one of the most common issues that critically ill patients experience. Medications used to manage agitation are often administered intravenously or intramuscularly in the acutely agitated, critically ill patient. However, a multimodal approach that utilizes multiple routes of administration may be appropriate. This review summarizes the available literature on oral antipsychotics, clonidine, and valproic acid to manage agitation in critically ill patients while also focusing on their pharmacology and appropriate monitoring. Despite inconclusive findings from different studies, antipsychotics, clonidine, and valproic acid may provide benefit for specific patient populations. As more evidence emerges, these agents may start playing a greater role in the management of agitation, which is not amenable to first-line agents. As health care professionals, it is prudent to be familiar with their dosing regimens, common adverse effects, and the monitoring required to maximize patient benefits and minimize harms.