In 2007, approximately 27,000 unintentional drug overdose deaths occurred in the United States, one death every 19 minutes. Prescription drug abuse is the fastest growing drug problem in the United States. The increase in unintentional drug overdose death rates in recent years has been driven by increased use of a class of prescription drugs called opioid analgesics. Since 2003, more overdose deaths have involved opioid analgesics than heroin and cocaine combined. In addition, for every unintentional overdose death related to an opioid analgesic, nine persons are admitted for substance abuse treatment, 35 visit emergency departments, 161 report drug abuse or dependence, and 461 report nonmedical uses of opioid analgesics. Implementing strategies that target those persons at greatest risk will require strong coordination and collaboration at the federal, state, local, and tribal levels, as well as engagement of parents, youth influencers, health-care professionals, and policy-makers.