This study used three generations and 21 years of prospective data to test models of intergenerational transmission of substance use and substance use risk. Thus, the study extends prior studies in the field that have focused predominantly on substance abuse. The association between the grandparental generation’s (G1 mother and father) and the parental generation’s (G2 father) (a) alcohol use and (b) illicit drug use was hypothesized to be mediated by G2’s poor inhibitory control. Additionally, we hypothesized that G1’s poor discipline of G2 would be directly associated with the G2’s substance use as well as partially mediate the association between G1’s substance use and G2’s inhibitory control. In turn, G2’s substance use in late adolescence was expected to be associated with their offspring’s (G3) poor inhibitory control at age 3 years. Findings partially supported the predictions and varied by substance. For alcohol use, only cross generational associations in use were found. For illicit drugs, both poor inhibitory control and poor discipline played some mediational role in cross-generational use.