Theories of acculturation predict that discrepancies in cultural orientation between adolescents and their parents will increase the adolescents' risk for behavior problems such as substance use. This study evaluated this hypothesis in a sample of 1772 Hispanic 9th grade students in Southern California. Parent–child discrepancy in U.S. orientation (defined as the difference between the child's U.S. orientation and the child's perception of the parents' U.S. orientation) was a risk factor for past-month smoking, lifetime and past-month alcohol use, and lifetime and past-month marijuana use. Parent–child discrepancy in Hispanic orientation (defined as the difference between the child's Hispanic orientation and the child's perception of the parents' Hispanic orientation) was a risk factor for lifetime and past-month alcohol and marijuana use. The adolescents' own Hispanic orientation was protective against lifetime and past-month smoking and marijuana use, but not alcohol use. In an analysis of mediation, U.S. acculturation discrepancy was associated with lower levels of family cohesion, which in turn was associated with higher levels of substance use. Results suggest that family-based interventions for acculturating and bicultural Hispanic families may be useful in decreasing the likelihood of substance use among Hispanic adolescents.