One of the main goals of the United Kingdom’s Drug Strategy is to reduce drug use among the most vulnerable groups of young people through the use of targeted prevention interventions. The effectiveness of these targeted prevention interventions hinge on the accurate identification of vulnerable groups and accurate knowledge regarding what causes drug use and what works to prevent it. Unfortunately, relatively little is known about how to prevent drug use among high-risk groups. This article presents a comprehensive and systematic evaluation of the research evidence regarding what works in terms of drug prevention among vulnerable groups of young people. Electron databases of predominantly published literature were searched using refined search strategies, producing a sample of 759 separate studies. Of these, only 16 studies were found that used a sound research design and involved a comparison group. Schools were the most common setting for prevention evaluations and the life-skills training interventions proved to be the most effective at reducing drug use in the short term. Among the interventions evaluated, most focused on youths aged 11 through 13 years. There is a need for more outcome evaluations of targeted prevention strategies in the United Kingdom; all of the studies evaluated here originated in North America. Table, references