Overdoses involving prescription drugs in the United States have reached epidemic proportions over the past 20 years.This review categorizes and summarizes literature on the topic dating from the first published reports through 2011 using a traditional epidemiologic model of host, agent, and environment.Host factors include male sex, middle age, non-Hispanic white race, low income, and mental health problems. Agent risk factors include use of opioid analgesics and benzodiazepines, high prescribed dosage for opioid analgesics, multiple prescriptions, and multiple prescribers. Environmental factors include rural residence and high community prescribing rates.The epidemiology of prescription drug overdoses differs from the epidemiology of illicit drug overdoses. Incomplete understanding of prescription overdoses impedes prevention efforts.This epidemic demands additional attention from injury professionals.