This longitudinal study examined whether adolescent personality characteristics and risk taking mediate the relationship between paternal substance dependence and adolescent substance use. At Time 1, the sample included 249 15-19 year-old adolescents and their fathers. These individuals also were assessed 5 years later (Time 2). Results indicated that paternal substance dependence directly and indirectly (via personality and risk taking) predicted adolescent substance use. Paternal substance dependence had significant direct effects on age when the adolescent first used marijuana and significant indirect effects on age when regular drinking began, age when first used marijuana, and frequency of drinking to get "high" or "drunk." All of the indirect personality effects were via adolescent disinhibition. In addition, adolescent risk taking further mediated personality and adolescent substance use. Results from this study are discussed in relation to an epigenetic perspective of human development.