The emergency department (ED) is commonly the first point of care for patients with acute behavioral issues from the community. Routinely, clinical management involves the use of benzodiazepine and/or antipsychotic drugs, when initial de-escalation strategies fail. There is currently scant literature available to inform the clinical management and resource utilization of acute agitation in the ED. This article discusses the approach to pharmacoeconomic studies of acute agitation management in the ED. It explores the conduct of such evaluations and highlights the cost and data sources required. The current difficulties experienced in conducting such evaluations are also discussed. Pharmacoeconomic studies related to the management of acute agitation in ED can be challenging. Robust clinical trials incorporating prospectively designed pharmacoeconomic studies will invariably contribute toward a better understanding of this therapeutic area and optimize the use of scarce resources.