The objective of this study was to evaluate the impact of a revised state-of-the-art drug prevention program, Project ALERT, on risk factors for drug use in mostly rural midwestern schools and communities. Fifty-five middle schools from South Dakota were randomly assigned to treatment or control conditions. Treatment-group students received 11 lessons in Grade 7 and 3 more in Grade 8. Effects for 4276 eighth graders were assessed 18 months after baseline. Results indicate that Project ALERT had statistically significant effects on all the targeted risk factors associated with cigarette and marijuana use and more modest gains with the pro-alcohol risk factors. The program helped adolescents at low, moderate, and high risk for future use, with the effect sizes typically stronger for the low- and moderate-risk groups. Thus, school-based drug prevention programs can lower risk factors that correlate with drug use, help low- to high-risk adolescents, and be effective in diverse school environments.