Cultural values can shape people's attitudes toward substance use and influence their risk of experimentation with drugs. This article examines the relationships between cultural values (familism, respeto, and machismo), fatalism (a culturally encouraged personality disposition), and substance use among Hispanic adolescents. In 2005, cross-sectional data were collected from 1,616 Hispanic ninth grade students in Los Angeles. Each cultural value was associated with lifetime substance use; however, these relationships depended on the type of substance and gender. Our findings suggest that it might be useful to incorporate the cultural values and address the personality trait of fatalism in prevention programs for Hispanic adolescents. The study's limitations are noted.