This study examined patterns of between-generation continuity in substance use from generation 1 (G1) parents to generation 2 (G2) adolescents and from G2 adult substance use and G1 substance use to generation 3 (G3) problem behavior in childhood. Structural equation modeling of prospective, longitudinal data from 808 participants, their parents, and their children showed low levels of G1 to G2 cross-generational continuity in the general tendency to use drugs. This effect was fully mediated by G2 early adolescent behavior problems. Drug-specific residual effects were observed across generations for cigarette smoking. Once established in adolescence, substance use in G2 showed stability over time. G2 substance use at age 27 significantly predicted G3 problem behavior. G1 substance use also was related to G3 problem behavior indirectly. These findings highlight the importance of interrupting intergenerational cycles of substance use and problem behavior.