This study evaluates the Drug Resistance Strategies (DRS) project, a culturally grounded, communication-based substance use prevention program implemented in 35 middle schools in Phoenix, Arizona. The intervention consisted of 10 lessons taught by the classroom teacher that imparted the knowledge, motivation, and skills needed to resist drug offers. The evaluation used growth modeling to analyze significant differences in average postintervention substance use (alcohol, cigarettes, and marijuana) and growth of use over the course of the study. The study involved 6,298 seventh graders (65% Mexican/Mexican American) who responded to at least 1 of 4 questionnaires (1 pretest and 3 follow-up measures). When compared to a control group, the DRS intervention appeared to significantly limit the increase in the number of students reporting recent substance use, especially alcohol and marijuana use. The multicultural version of the curriculum proved most broadly effective, followed by the version targeting Mexican American youth. The development of a culturally grounded prevention curriculum for Mexican American youth expands the population being served by interventions. Moreover, the success of the multicultural curriculum version, which has the broadest application, provides particular promise, and the article demonstrates how a growth modeling approach can be used to evaluate a communication-based intervention by analyzing changes over time rather than differences between the pretest and posttest scores.