Group-randomized trials (GRTs)--studies that evaluate the efficacy or effectiveness of interventions occurring at the group level--are increasingly used to assess the effects of school-based prevention programs on behavioral outcomes of children and adolescents. These designs pose many implementation and design challenges for school administrators, teachers, and researchers. This article discusses issues associated with the use of GRTs in school-based prevention experiments. Lessons learned from the Youth Matters prevention study, a GRT currently being conducted in 28 urban elementary schools, are outlined. Implications of GRTs for practice and research are noted.