Research is limited or absent on Mexican adolescents' exposure to substance offers, ways of dealing with these offers, and possible gender differences in responses to offers. Extending U.S.-based research, this study examines how youth living in the Mexican state of Guanajuato employ the four drug resistance strategies--refuse, explain, avoid, and leave--that are part of the Keepin' It REAL evidence-based drug prevention intervention. The analysis uses cross-sectional survey data from 702 students enrolled in eight alternative secondary education sites in 2007. Participants reported the drug resistance behaviors they used to deal with offers of alcohol, cigarettes, and marijuana. Using multivariate regression, findings indicate most youth had developed repertoires of drug resistance strategies that involved multiple REAL strategies and some other strategy as well. For those receiving offers, the most common strategy was to refuse the offer with a simple "no." However, males used all the strategies significantly more often than females for situations involving cigarettes and marijuana as well as when using refuse and non-REAL strategies for alcohol. Possible reasons for the gender difference in use of strategies are discussed. The findings can help inform effective prevention programs based on teaching culturally appropriate drug resistance and communication skills.