This paper examines drug use trends and patterns among U.S. military personnel with an emphasis on prescription drug misuse (i.e., nonmedical use) and prescription pain medication misuse. Data were drawn from the large-scale population-based U.S. Department of Defense Surveys of Health Related Behaviors among Active Duty Military Personnel. Assessment of trends showed large reductions in illicit drug use (including prescription drug misuse) from 1980 to 2002. From 2002 to 2008, prescription drug misuse increased. The key driver of the high rates of past-month prescription drug misuse in 2008 (11%) was past-month misuse of pain medications (10%). The strongest predictor of prescription pain medication misuse was having a prescription for pain medication. Holders of prescriptions for pain medications were nearly three times more likely to misuse prescription pain relievers than those who did not have a prescription. Being in the Army, meeting criteria for Posttraumatic Stress Disorder (PTSD), and engaging in heavy alcohol use were also strong predictors of pain medication misuse. Findings suggest that easy access to pain medications is a key factor in misuse and that better education about the dangers of misusing prescription pain relievers and closer monitoring of prescription drugs may be needed to decrease misuse. Further studies are needed to determine the nature and extent of pain medication misuse, the characteristics of misusers, and their motivations for misuse. Additional research is also needed to develop and implement targeted interventions that reduce misuse of pain medications.