This chapter summarizes the current state of the art with respect to school-based drug misuse prevention. The chapter begins by presenting an historical overview of prevention, including summarizing drug use trends based on national surveillance data. The chapter then includes a brief overview outlining the principles of social learning and self-efficacy theories of human motivation, both of which have played a central role in guiding the development of many current prevention models. Several real-world barriers to program implementation are also discussed. In particular, the chapter discusses procedures for ensuring that programs are culturally sound, including discussion of whether deep versus surface structure changes are required to effectively deliver prevention to ethnic or racial subgroups. The various steps required to achieve cultural sensitivity are illustrated using the keepin’ it REAL prevention program. The chapter then explores manipulation checks showcasing how program evaluations use mediation analyses to empirically confirm the active ingredients of drug prevention. The chapter also discusses the need for longitudinal follow-up to establish durable program effects and provides several evidence-based examples drawn from smoking and other drug prevention studies. The chapter closes by summarizing concerns with implementation, the role of teachers in program delivery, and capacity building, all of which influence program outcomes.