A conceptual elaboration was developed that incorporates many risk and protective factors, and both direct and moderating (buffering) influences on drug involvement were tested. From prospective data, 14 factors related to drug use were selected and assigned empirically to either a multiple protective index (PFI) or a risk factor index (RFI). Analyses examined the relationships of the RFI, PFI, and their interaction on measures of cigarette, alcohol, cannabis, cocaine, and hard drug use cross-sectionally in late adolescence and later in young adulthood. These same variables were used to predict alcohol, cannabis, and cocaine abuse 8 years later. Vulnerability as measured by the RFI, PFI, and their interaction was highly associated with drug use in adolescence, moderately associated with certain types of drug use in young adulthood, and strongly associated with heightened drug problems in adulthood.