Using an ecodevelopmental framework, we examined how peer, parent, and student variables influence substance (tobacco, alcohol, and marijuana) use among rural and urban Latino/a adolescents (N = 2,500). Generally speaking, Latino/a adolescents in rural areas endorsed higher levels of substance use. Among the primary variables of study, there were a number of nuanced differences noted based on location, gender, and type of substance. Peer use was related to individual substance use in both rural and urban areas. However, peer use was a significantly stronger predictor of tobacco use among rural Latinas than urban dwelling. Parental monitoring was not predictive of urban marijuana use, yet was negatively associated with substance use for all subgroups and was especially pronounced for female alcohol use. Parental emotional involvement predicted higher alcohol use among urban boys. School achievement was negatively associated with substance use for all subgroups while, conversely, school involvement was associated with higher alcohol use for rural boys. Cultural and contextual implications for intervention and prevention are discussed.