This study explored the drug resistance strategies that urban American Indian adolescents consider the best and worst ways to respond to offers of alcohol, cigarettes, and marijuana. Focus group data were collected from 11 female and 9 male American Indian adolescents attending urban middle schools in the southwest. The youth were presented with hypothetical substance offer scenarios and alternative ways of responding, based on real-life narratives of similar youth. They were asked to choose a preferred strategy, one that would work every time, and a rejected strategy, one they would never use. Using eco-developmental theory, patterns in the preferred and rejected strategies were analyzed to identify culturally specific and socially competent ways of resisting substance offers. The youth preferred strategies that included passive, non-verbal strategies like pretending to use the substance, as well as assertive strategies like destroying the substance. The strategies they rejected were mostly socially non-competent ones like accepting the substance or responding angrily. Patterns of preferred and rejected strategies varied depending on whether the offer came from a family member or non-relative. These patterns have suggestive implications for designing more effective prevention programs for the growing yet underserved urban American Indian youth population. (Contains 3 tables and 1 figure.)