Background: When well-designed and implemented, cluster randomized trials can meet the high standards federal agencies and other funders increasingly require for evidence on the effectiveness of school health programs and services. However, designing and implementing these studies can present more challenges than at first appears. Methods: I reviewed summaries of the methodological literature on cluster randomized trials. I then conducted a search to identify practical applications of these methods in school health research. Results: The review identified 6 key issues or decisions school health researchers must address when designing, conducting, and analyzing data from a cluster randomized trial: (1) reasons to use a clustered design, (2) sample size calculation, (3) the use of matching or stratification, (4) definition of the school and student samples, (5) consent gathering, and (6) analysis methods. Conclusions: School health researchers can take several practical steps to ensure the availability of high-quality research evidence and meet the growing demands for evidence and accountability in education policy and programming. These steps include selecting the right research design for the intervention and evaluation setting, identifying appropriate sample definitions and analysis methods, and developing appropriate procedures for gathering parental permission and student assent.