Although social context has been implicated in substance use and misuse, a complex literature has developed around the precise role that living in an urban or rural setting might have in the development of these behaviors. In particular, studies simplistically comparing urban versus rural in univariate analyses, and failing to control for potential confounds, have been criticized. One such potential confound is the location of the school that individuals attend. The present study used a large adolescent sample to examine the relationship between city, intermediate, and rural living on use of a range of substances. Results suggest an influence of both home and school locations, with (generally speaking) attending a less academically focused city-based school being significantly associated with increased substance use. Being male also was associated with increased substance use. However, the results also point to the substance-specific nature of the results, in particular to the more normative use of alcohol compared with the use of cigarettes and controlled drugs. Results are discussed in the context of prevention and health promotion initiatives.