In the United States, the nonmedical use of prescription drugs is the second most common illicit drug use, behind only marijuana. This article discusses the abuse issues with three of the most widely abused prescription drugs: opioids, central nervous system (CNS) depressants (eg, benzodiazepines), and stimulants (eg, amphetamine-dextroamphetamine and methylphenideate) in the United States. Efforts to deal with the problem are described as well.