Recent advances in prevention science provide evidence that adolescent health and behavior problems can be prevented by high-quality prevention services. However, many communities continue to use prevention strategies that have not been shown to be effective. Studying processes for promoting the dissemination and high-quality implementation of prevention strategies found to be effective in controlled research trials has become an important focus for prevention science. The Communities That Care prevention operating system provides manuals, tools, training, and technical assistance to activate communities to use advances in prevention science to plan and implement community prevention services to reduce adolescent substance use, delinquency, and related health and behavior problems. This paper describes the rationale, aims, intervention, and design of the Community Youth Development Study, a randomized controlled community trial of the Communities That Care system, and investigates the baseline comparability of the 12 intervention and 12 control communities in the study. Results indicate baseline similarity of the intervention and control communities in levels of adolescent drug use and antisocial behavior prior to the Communities That Care intervention. Strengths and limitations of the study's design are discussed.