Shifting patterns of substance use (that is, early initiation, increased marijuana use, narrowing differences in gender use) and the disproportionate socioeconomic obstacles that are related to substance use among ethnically diverse adolescent females create the need to develop ethnic and gender-specific substance use prevention frameworks. This article describes and applies a substance use prevention framework to African American females. Gender socialization and self-efficacy are presented as key concepts, along with the assertion that every substance use prevention framework should examine the influences of specific societal factors (such as racism, sexism, classism, and ageism) on substance use. Rationale and guidelines for designing ethnically sensitive and gender-specific research projects and intervention programs regarding substance use prevention are offered. Public health nurses (PHNs) are uniquely positioned to use this framework in their work with African American adolescent girls, specifically, and in general with other ethnically diverse groups.