The diffusion of school-based preventive interventions involves the balancing of high-fidelity implementation of empirically-supported programs with flexibility to permit local stakeholders to target the specific needs of their youth. There has been little systematic research that directly seeks to integrate research- and community-driven approaches to diffusion. The present study provides a primarily qualitative investigation of the initial roll-out of two empirically-supported substance and violence prevention programs in two urban school districts that serve a high proportion of low-income, ethnic minority youth. The predominant ethnic group in most of our study schools was Asian American, followed by smaller numbers of Latinos, African Americans, and European Americans. We examined the adaptations made by experienced health teachers as they implemented the programs, the elicitation of suggested adaptations to the curricula from student and teacher stakeholders, and the evaluation of the consistency of these suggested adaptations with the core components of the programs. Data sources include extensive classroom observations of curricula delivery and interviews with students, teachers, and program developers. All health teachers made adaptations, primarily with respect to instructional format, integration of real-life experiences into the curriculum, and supplementation with additional resources; pedagogical and class management issues were cited as the rationale for these changes. Students and teachers were equally likely to propose adaptations that met with the program developers’ approval with respect to program theory and implementation logistics. Tensions between teaching practice and prevention science—as well as implications for future research and practice in school-based prevention—are considered.