Cultural adaptation may influence Latino youth substance use (SU) development, yet few longitudinal studies have examined cultural change over time and adolescent SU outcomes. Using longitudinal data collected annually across ages 10-16 from 674 Mexican-origin youth (50% female), the authors characterized cultural adaptation patterns for language use (English and Spanish use), values (American values and familism values), and identity (ethnic pride), and examined whether these cultural adaptation patterns were associated with differential SU risk. Youth with increasing bilingualism and high/stable family values had lower SU risk compared to youth who primarily spoke English and endorsed decreasing family values, respectively. Ethnic pride trajectories were not associated with SU. Findings highlight the importance of considering cultural change related to Latino youth SU.