This manuscript reports on the development and evaluation of a computer-based substance abuse prevention program for middle school-aged adolescents, called "HeadOn: Substance Abuse Prevention for Grades 6-8TM". This self-guided program was designed to deliver effective drug abuse prevention science to youth via computer-based educational technologies that effectively promote learning of key skills and information. Results of a controlled, school-based evaluation demonstrated that the HeadOn substance abuse prevention program promoted significantly higher levels of accuracy in objective knowledge about drug abuse prevention relative to the demonstrably effective Life Skills Training Program. Participants in the "HeadOn" and Life Skills groups also generally achieved comparable, positive outcomes after completing their substance abuse prevention intervention in actual self-reported rates of substance use, intentions to use substances, attitudes toward substances, beliefs about prevalence of substance use among both their peers and adults, and likelihood of refusing a drug offer. The "HeadOn" program may be of substantial benefit in providing drug abuse prevention to middle school-aged youth in a manner that ensures the fidelity of the intervention. It may also provide comprehensive substance abuse prevention science that is more cost-effective than the labor-intensive prevention interventions that have been demonstrated to be efficacious, and thereby expand the reach of effective drug abuse prevention science.