Examined the chronological and statistical relations among onsets of psychopathology, alcohol and cannabis use, and substance-related problem psychopathology, alcohol and cannabis use, and substance-related problems from late childhood through early adolescence in boys of fathers with substance use disorder (SUD; high average risk: n = 177) and without SUD (low average risk: n = 203) using survival analysis. Proportional hazard models indicated that antisocial disorders were predicted by risk group and mediated the observed relation between risk group and substance-related problems. Negative affect disorders were predicted by risk group but did not predict substance involvement in early adolescence. Results support a model in which paternal SUD predisposes to increased antisocial and negative affect disorders in boys, and antisocial disorders lead to substance-related problems in early adolescence.