This prospective investigation examined the contribution of neighborhood context and neurobehavior disinhibition to the association between substance use disorder (SUD) in parents and cannabis use disorder in their sons. It was hypothesized that both neighborhood context and son's neurobehavior disinhibition mediate this association. Two hundred and sixteen boys were tracked from ages 10-12 to age 22. The extent to which neighborhood context and neurobehavior disinhibition mediate the association between parental SUD and son's cannabis use disorder was evaluated using structural equation modeling. The best fitting model positioned neighborhood context and neurobehavior disinhibition as mediators of the association between parental SUD and cannabis use disorder in sons. Neurobehavior disinhibition also was a mediator of the association between neighborhood context and son's cannabis use. The implications of this pattern of association between parental SUD, neighborhood context and individual risk for SUD for improving prevention are discussed.