The Three Generational Study (3GS) began in the early 90s and involves the third generation (G3) offspring of second generation (G2) fathers who were originally recruited in 1984 as part of the Oregon Youth Study (OYS) in mid childhood (ages 9–10 years) along with their first- generation (G1) parents. As boys, the G2 fathers lived in higher delinquency neighborhoods of a medium-sized Pacific Northwestern United States city. The OYS–3GS examines questions concerning socially mediated intergenerational transmission versus discontinuity (or moderation) of antisocial behavior, substance use, and related problem behaviors. Questions address influences of the grandparents, or Generation 1 (G1), on their sons in G2 and in turn of these sons and their partners on their own children in G3. In this article, we present an overview of the study design—and underlying theory—related to general and outcome-specific transmission pathways. We then summarize key issues and findings to date related to the current main focus of the study regarding intergenerational associations in substance use.