This study examines gender differences in the use of drug resistance strategies for rural Asian/Pacific Islander youth. Multiethnic Asian/Pacific Islander youth (N = 213) from six middle/intermediate schools on the Island of Hawai‘i participated in the study, and gender differences in their real-world use of specific strategies (e.g., refuse, explain, avoid, leave) were examined. Despite similar levels of exposure to situations where drugs and/or alcohol were offered, girls indicated significantly lower usage of most of the resistance strategies compared to boys, suggesting girls’ increased risk in dealing with drug-related problem situations. Implications for gender-and culture-specific health promotion and drug prevention curricula are discussed.