This chapter argues that a major challenge for the field of drug-abuse prevention is making sure interventions are aimed at the right targets, high-potential mediators. The field of drug-abuse prevention is vast and consists of many different prevention approaches, types of interventions, target populations, and behavioral outcomes. The new agenda for evaluation begins by recognizing that interventions like drugabuse prevention programs are often complex and multidimensional, and aspire for indirect effects on drug use behavior. Knowledge about drug-abuse prevention is generally based on three types of research: preintervention research, efficacy research, and effectiveness research. The chapter focuses on one of the popular and challenging drug prevention problems, the primary prevention of the onset of adolescent substance use. Interventions designed to prevent the risk factors are presumed to lower rates of adolescent drug-abuse. A series of evaluations is sometimes needed to fully understand mediating and moderating effects of drug-abuse prevention interventions.