Objective To examine the lifetime prevalence of medical and nonmedical use of prescription stimulants (e.g., Adderall, Concerta, Ritalin, Dexedrine) among high school seniors in the United States, and to assess substance use behaviors (i.e., cigarette smoking, binge drinking, marijuana, and other drug use) based on lifetime histories of medical and nonmedical use of prescription stimulants. Method Nationally representative samples of high school seniors from the Monitoring the Future study were surveyed via self-administered questionnaires. The sample consisted of 4,572 individuals (modal age 18 years) from 2 independent cohorts (2010 and 2011) and represented a population that was 50% female, 57% white, 12% African-American, 13% Hispanic, and 18% other. Results The lifetime prevalence of medical use of prescription stimulants was 9.5%, and the lifetime nonmedical use of prescription stimulants was also 9.5%. Among those who were ever prescribed stimulants, approximately 59.3% reported medical use only, 22.9% reported medical use before nonmedical use, and 17.8% reported nonmedical use before medical use. The odds of substance use behaviors generally did not differ between medical users only and non-users. In contrast, the odds of substance use behaviors were greater among nonmedical users only and medical users who reported any history of nonmedical use relative to nonusers. Conclusions About 1 in every 6 high school seniors in the United States has ever had some exposure to prescription stimulants, either medically or nonmedically. Health care professionals should carefully screen and monitor adolescents, because the risk for substance abuse is directly associated with a history of nonmedical use of prescription stimulants.