This article reviews the literature on school-based universal violence prevention programs to illustrate key methodological challenges for investigating subgroup differences in prevention effects. The variety of potential moderating factors examined within this literature is discussed within the context of a social-ecological model. Our review of this literature identified the following methodological issues: the need for a clear a priori theoretical basis for selecting potential moderators, inflated Type I error rates that result from large numbers of comparisons, the absence of explicit tests of moderation, interpretive issues arising from a restricted range on moderator variables, the failure to report effect size estimates, the presence of potential confounding factors, and the importance of examining factors that might operate at multiple ecological levels. These points are illustrated using examples of studies, primarily within youth violence prevention research, that have identified factors within the individual, school, and community that moderate the outcomes of preventive interventions. We conclude with general recommendations for future work. These include the benefits of using the social-ecological model to provide a basis for moving from exploratory to more theory-driven confirmatory models of subgroup differences, the potential merits of qualitative research designed to identify factors that may influence the effectiveness of intervention efforts for specific subgroups of individuals, and the provision of effect size estimates and confidence intervals for effect sizes in prevention reports.