Evidence demonstrates that adolescent substance use is prevalent and extends to adolescents of immigrant minority groups. Given the large presence and growth of Hispanic-Latino and Asian populations in the United States, examining the role of culturally specific experiences in substance use risk among Hispanic-Latino and Asian adolescents is critical. In particular, evidence indicates that acculturation may pose particular challenges for Hispanic-Latino and Asian adolescents, thereby increasing risk for substance use. This review aims to synthesize existing evidence for the role of acculturation in substance use and the proposed mechanisms underlying this relation among Hispanic-Latino and Asian adolescents. Based on this review, the implications of this evidence on future research and the development and implementation of substance use interventions for Hispanic-Latino and Asian adolescents are discussed.