Abstract
Clear evidence supports a genetic basis for substance use disorders (SUD). Yet, the search to identify individual gene contributions to SUD has been unsuccessful. Here, we argue for the study of endophenotypes within the frame of individual differences, and identify three high-order personality traits that are tied to specific brain systems and genes, and that offer a tractable approach to studying SUD. These personality traits, and the genes that moderate them, interact dynamically with the environment and with the drugs themselves to determine ultimately an individual's vulnerability or resilience to developing SUD.