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This study seeks to examine the moderating effects of cultural values (Latino values and mainstream American values) on the relations among parenting factors, substance use, and aggression among Latino adolescents using a longitudinal design. Data were collected from 213 Latino 10th graders between October 2011 and May 2012 and were analyzed using path analyses. Latino values at Time 1 negatively predicted substance use norms at Time 2, while mainstream American values at Time 1 positively predicted substance use amount at Time 2, after controlling for substance use at Time 1. Latino values moderated the relations between parental monitoring and substance use. Parental monitoring predicted more substance use among adolescents who reported lower Latino values, but not for adolescents who reported higher Latino values. Mainstream American values moderated the relations between parent-child conflict and substance use. Parent–adolescent conflict predicted more substance use among adolescents who reported higher mainstream American values, but not for adolescents who reported lower mainstream American values. The effects of parental monitoring and parent-child conflict on adolescent substance use are contingent on cultural values. Mainstream American values may enhance the risk of parent-adolescent conflict, whereas Latino values may enhance the protection of parental monitoring in relation to substance use. Highlights: Higher mainstream American values and lower Latino values predicted later substance use. Mainstream American values interacted with parent-adolescent conflict to predict substance use. Parenting operates in the context of adolescents' cultural values to predict substance use. [ABSTRACT FROM AUTHOR]