The primary purpose of this study was to examine the extent to which two of the three sources of risk-taking—dispositional and ecological—in adolescence and demographic variables were related to Ritalin, tranquilizer and narcotics misuse. The secondary aim of this study was to distinguish subgroups of Ritalin, tranquilizer, and narcotics misusers using dispositional, ecological and demographic variables. An archival dataset containing 1672 participants (11–18 years old) was used. Ritalin, tranquilizer, and narcotics misuse were dichotomized and hierarchical logistic regressions were computed for dispositional and ecological sources of risk-taking and demographics. To distinguish subgroups of misusers, hierarchical multinomial regressions were computed. Dispositional, ecological, and demographic variables were related to Ritalin, tranquilizer, and narcotics misuse and distinguished among non-users, experimenters/occasional misusers, and frequent misusers. Prescription drug prevention programs should incorporate demographic, dispositional, and ecological variables and should parallel the guidelines currently used for developing effective substance abuse prevention programs.