This study explored how a non-targeted group of ethnic minority youth might or might not benefit from a prevention intervention focused on other cultural groups. The study specifically evaluated the effects of an evidence-based drug prevention curriculum with a sample of urban American Indian youth in the southwest U.S., most of whom self-reported multi-ethnic heritages. Using growth curve modeling, this research examined the developmental trajectory of drug use for these youth, and compared it with the trajectory of youth from other racial/ethnic groups at pre-intervention, post-intervention, and two follow up time periods. Results indicate that alcohol and marijuana use increased from pre-intervention across subsequent time periods for all youth. The drug use of the American Indian youth in the treatment group increased on some measures. Specifically, they reported a steeper trajectory in the amount and frequency of alcohol and marijuana use compared to the youths in the treatment groups with other racial/ethnic identifications. The implications of these findings for the development of culturally grounded prevention programs for multi-ethnic, urban American Indian youth are discussed. Editors’ Strategic Implications: This research provides a specific example, but also makes a strong global argument, for the need to develop and evaluate prevention programs that are culturally grounded in the worldview of the target group.