Prevention research continues to focus on school-based substance use programs aimed at adolescents. These programs are designed to reduce substance use and risk behavior by targeting key mediators, such as normative beliefs, which in turn reduce substance use. All Stars is a newly developed program that was recently evaluated in a randomized field trial in 14 middle schools in Lexington and Louisville, Kentucky. The authors examined targeted and nontargeted variables as possible mediators of program effectiveness. Findings indicate that All Stars achieved reductions in substance use and postponed sexual activity when teachers were successful at altering targeted mediators: normative beliefs, lifestyle incongruence, and manifest commitment to not use drugs. The program was not successful when it was delivered by specialists. At least in part, this failure is attributable to specialists' inability to change mediators as intended by the program. (Contains 3 tables and 1 figure.)