In this study, the effects of neighborhood-level risk factors and family mobility on adolescent substance use were examined using a high-risk sample of children of alcoholics and demographically matched controls. Although there were no direct effects of the neighborhood predictors or family mobility on any of the substance use outcomes in the full model, multiple group analyses found several prospective effects within the COA and non-COA subgroups. Among non-COAs, neighborhood SES positively predicted alcohol use and alcohol consequences, while family mobility negatively predicted externalizing symptoms. Among COAs, neighborhood SES negatively predicted drug use onset and was marginally negatively predictive of alcohol use and consequences, while family mobility positively predicted drug use and drug consequences. The findings from the current study highlight three overarching conclusions of interest: (1) Neighborhoods influence developing adolescents differently depending on their level of family risk of alcoholism, (2) Neighborhood SES and family mobility have differential effects on adolescent substance use outcomes, and (3) Neighborhood SES and family mobility are meaningful predictors of adolescent substance use that could be meaningful targets for prevention and intervention efforts.