Aims To identify the developmental course of non-medical use of four separate prescription drug classes (opioids, sedatives, stimulants and tranquilizers) by examining the general functional growth and related covariates during the transition from adolescence to adulthood in the United States. Design Nationally representative probability samples of high school seniors were followed longitudinally across five waves (waves 1, 2, 3, 4 and 5: modal ages 18, 19/20, 21/22, 23/24 and 25/26 years, respectively). Setting Data were collected via self-administered questionnaires to high school seniors and young adults in the United States. Participants The sample consisted of nearly 72 000 individuals in 30 cohorts (high school senior years of 1977-2006) who participated in at least one wave. Measurements Self-reports of annual non-medical use of prescription opioids, sedatives, stimulants, and tranquilizers. Findings The annual non-medical use of prescription opioids, sedatives, stimulants and tranquilizers was highest at wave 1 over the five waves. There was a consistent descending path (linear and quadratic slopes, P < 0.001) in annual non-medical use from baseline across all four prescription drug classes (e.g. opioids linear slope = −0.043 and opioids quadratic slope = 0.034, P < 0.001). While the annual non-medical use of stimulants declined over time (linear slope = 0.063, P < 0.01; quadratic slope = −0.133, P < 0.001), the same decrease was not observed for the annual non-medical use of prescription opioids, sedatives or tranquilizers when controlling for socio-demographic and substance use behaviors at baseline. The covariates associated with the general functional growth differed across the four prescription drug classes. Conclusions The non-medical use of prescription opioids, sedatives, stimulants and tranquilizers appears to peak during late adolescence, suggesting preventive intervention efforts should be initiated in early adolescence. The developmental course of non-medical use is not the same among all four classes of prescription drugs, suggesting that each drug class warrants individual research.