Drawing from developmental and cultural adaptation perspectives and using a longitudinal design, this study examined: (a) mean-level changes in Mexican-origin adolescents’ cultural orientations and adjustment from early to late adolescence and (b) bidirectional associations between cultural orientations and adjustment using a cross-lag panel model. Participants included 246 Mexican-origin, predominantly immigrant families that participated in home interviews and a series of nightly phone calls when target adolescents were 12 and 18 years of age. Girls exhibited more pronounced declines in traditional gender role attitudes than did boys, and all youth declined in familism values, time spent with family, and involvement in Mexican culture. Bidirectional relations between cultural orientations and adjustment emerged, and some associations were moderated by adolescent nativity and gender.