Although previous research has identified links between parenting and adolescent substance use, little is known about therole of adolescent individual processes, such as sensation seeking, and temperamental tendencies for such links. To testtenets from biopsychosocial models of adolescent risk behavior and differential susceptibility theory, this study investigatedlongitudinal associations among positive and harsh parenting, adolescent sensation seeking, and substance use and testedwhether the indirect associations were moderated by adolescent temperament, including activation control, frustration,sadness, and positive emotions. Longitudinal data reported by adolescents (n = 892; 49.66% girls) and their mothers fromeight cultural groups when adolescents were ages 12, 13, and 14 were used. A moderated mediation model showed thatparenting was related to adolescent substance use, both directly and indirectly, through sensation seeking. Indirectassociations were moderated by adolescent temperament. This study advances understanding of the developmental pathsbetween the contextual and individual factors critical for adolescent substance use across a wide range of cultural contexts.