The consequences of the early onset of substance use on later outcomes are a public health concern. In the present study, we examined neighborhood risk factors as a possible predictor of the onset of substance use in adolescents. In addition, we assessed the potential buffering effects of parental supervision on the relationship between neighborhood risk and the onset of substance use. The participants included 95, abstinent, African American 6th graders (mean age = 11.5 years) who enrolled in one site of a national, multi-site study of high-risk youth participating in a federally sponsored program. In the 6th and 8th grades, the participants completed self-report measures regarding substance use, perceived negative neighborhood activities and parental supervision. Logistic regression analyses demonstrated that both exposure to negative neighborhood activities and low parental supervision increase the onset of substance use by the 8th grade among African American adolescents. However, the results suggested that parents can protect their adolescents from the impact of exposure to adverse neighborhood factors by providing appropriate supervision.