This study tests the applicability among adolescents in Mexico of the keepin' it REAL (refuse, explain, avoid, and leave) strategies that are common and effective ways that U.S. youth resist substance use. Following a social learning, communication competence and ecological theory integrated approach, the study draws on self-reported questionnaire data from a non-probability sample of 327 adolescents attending two public high schools in Monterrey, Nuevo León. Multivariate regressions were used to test whether the respondents' use of the REAL strategies by the participants could be predicted by key demographic variables. Separate models were estimated for the frequency of use of each strategy and for different substances. Findings indicate that most adolescents in this sample utilized each of the REAL strategies as well as other strategies to respond to offers of alcohol, cigarettes, or marijuana. Mexican and U.S. youth residing close to the US border appear to use similar drug resistance strategies. Use of the strategies varied considerably by the level of exposure to offers, but only minimally by gender and age. There were no notable differences by socioeconomic status or academic performance. Implications for prevention science, social work practice and social work research are discussed in the context of the bi-national border region and the applicability and prospect for dissemination of U.S. evidence based youth substance use prevention interventions.