Objectives: This is a review and evaluation of the current clinical guidelines and empirical literature in relation to the Department of Defense (DoD) policies and directives regarding prescription drug misuse (PDM). Methods: Sources were 11 clinical guidelines and consensus statements, 20 DoD Directives and the published literature from 2000 to 2012. Articles were included if they specifically focused on the prevention or treatment of PDM. Results: DoD directives were evaluated in relation to the clinical guidelines and the relevant research literature. Empirical evidence supporting the directives was limited. Conclusions: There is little empirical evidence for the prevention and treatment of PDM and the majority of published guidelines and studies focus on prescription opioids. Important limitations include the lack of information about appropriately identifying and managing persons at risk for PDM. More research is needed to identify and recommend effective mechanisms for the prevention and treatment of PDM.