Family interactional theory, primary socialization theory, the social developmental model, and differential acculturation theory inform a conceptual framework explaining Latina/o adolescent substance use. Structural equation modeling is used to empirically test structural relationships constituting risk and protective factors, as well as the influence of participation in Corazón de Aztlan (“Heart of My People”), a culturally competent substance use prevention program developed for Latina/o adolescents. Youth reporting higher conflict with family reported higher peer conflict, which was positively associated with greater youth substance use. Greater family substance use was associated with greater peer substance use, which was associated with greater youth substance use. Youth reported less substance use after participating in Corazón de Aztlan.