Understanding how culture and familial relationships are related to Mexican-origin youths' normative sexual development is important. Using cultural-ecological, sexual scripting, and risk and resilience perspectives, the associations between parent-adolescent relationship characteristics, adolescents' cultural orientations and familism values, and sexual intentions among 246 Mexican-origin adolescents (50% female) were investigated. Regression analyses were conducted to examine the connections between youths' cultural orientations and familism values and their intentions to engage in sexual intercourse and to test the moderating role of parent-adolescent relationship characteristics and adolescent sex. For boys, under conditions of high maternal acceptance, higher Anglo orientations and higher Mexican orientations were related to greater sexual intentions. For girls, familism values played a protective role and were related to fewer sexual intentions when girls spent less time with their parents. The findings highlight the complex nature of relationships between culture, family relationships, and youths' sexual intentions and different patterns for girls versus boys.