This study modeled direct and mediated pathways linking childhood hyperactivity and substance use disorder (SUD). Boys (n = 112) were administered the revised Drug Use Screening Inventory at age 12-14 years and the Structured Clinical Interview for DSM-IV at age 22 years. Six newly derived scales having established heritability were conceptually organized into internalizing and externalizing pathways to SUD emanating from childhood hyperactivity. Hyperactivity directly predicts SUD. Neuroticism, conduct problems, and their respective manifestations of social withdrawal and school problems mediated the association between hyperactivity and SUD. Hyperactivity also predicted neuroticism that, in turn, predicted low self-esteem leading to social withdrawal and SUD. These results indicate that hyperactivity is a diathesis for both internalizing and externalizing disturbances that, in turn, portend differential expression of psychosocial maladjustment presaging SUD.