Communities are the context in which many prevention activities take place. One approach to community prevention is to identify the most elevated risk factors and most depressed protective factors for substance use in a community and then to select and implement preventive interventions to address the most elevated risk factors and most depressed protective factors in the community. This approach presumes that there are reliable differences between communities in risk and protection and that these differences relate to differences in substance use across communities. This paper addresses these issues using data from 28,091 students in 41 communities across the U.S. Intraclass correlation coefficients are used to assess the degree to which there are reliable and meaningful differences between communities in levels of risk and protective factors. The community means of the risk and protective factors are then correlated with levels of substance use. Findings indicate that there are meaningful differences between communities in levels of specific risk and protective factors, and that those differences are related to different levels of substance use in these communities. These results provide an empirical foundation for tailoring community-wide efforts to prevent substance abuse to the specific profiles of risk and protective factors experienced by youths in different communities.