The emergence of clinically efficacious prescription drugs to treat pain, anxiety, and learning disorders is accompanied by the potential for nonmedical use. Prescription drug abuse has become a modern-day epidemic in the United States and is now second only to marijuana use across all age groups. This article reviews the various data collection, analysis, and reporting systems that have been developed in response to the growing concern for nonmedical prescription drug use. The terminology used to categorize prescription drugs that are abused and the various definitions for abuse, misuse, and nonmedical use are discussed. The epidemiology of nonmedical prescription drug use and an overview of each class of prescription drug that is at risk for nonmedical use are presented along with details of specific drugs that are associated with significant morbidity or mortality.