This study determined the relevance of preadolescent psychopathology and substance use for predicting early adolescent alcohol and cannabis involvement in boys of fathers with and without substance use disorders (SUD). Fathers of preadolescent boys (ages 10 through 12 years) were recruited to represent families of boys with paternal SUD (High Risk or HR: N = 102) and boys without paternal SUD (Low Average Risk or LAR: n = 166). These boys and a parental informant participated in semistructured diagnostic interviews at baseline and 2-year follow-up assessments (ages 12 through 14 years). Preadolescent tobacco experimentation and early adolescent regular alcohol use were more prevalent in HR than in LAR subjects. Logistic regression analyses were utilized to develop prediction equations. The presence of oppositional defiant disorder and the absence of anxiety disorders predicted preadolescent tobacco use. Preadolescent conduct disorder predicted early adolescent regular alcohol use. Preadolescent tobacco use and conduct disorder were highly predictive of early adolescent cannabis use, achieving 100% sensitivity with 76% specificity. Children with tobacco use prior to adolescence, as well as those with disruptive behavior disorders, may be important to target for interventions to prevent cannabis use.