Drug abuse continues to be an important public health problem throughout the world. Although considerable progress has been made in identifying effective prevention approaches, there is a large gap between what research has shown to be effective and the methods generally used in most schools. The most promising prevention approaches target individuals during the beginning of adolescence and teach drug resistance skills and norm setting either alone or in combination with general personal and social skills. Evaluation studies testing these approaches show that they can significantly reduce adolescent tobacco, alcohol, and marijuana use. While some studies show that these effects may decrease over time, booster interventions have been found to maintain and in some instances even enhance prevention effects. The results of one large-scale evaluation study shows that it is possible to produce reductions in drug use that last until the end of high school. Available evidence suggests that these approaches may be effective when taught by different kinds of teachers and with different populations. The current paper provides a brief review of school-based prevention approaches targeting individual-level etiologic factors, evidence supporting their effectiveness, and a discussion of potential mediating mechanisms.