Drug abuse, or substance abuse, is a substantial public health problem in the United States, particularly among high school students. The purpose of this article was to review school-based programs implemented in high schools for substance abuse prevention and to suggest recommendations for future interventions. Included were English language publications indexed in PubMed, CINAHL, or ERIC databases, between 2005 to November 2012, involving high school settings focused on prevention of drugs, and using a quantitative design for evaluation. A total of 18 studies met the criteria with 12 different interventions. Seven interventions were able to demonstrate statistically significant changes from before, to after the intervention, with regard to substance use. Recommendations for future interventions have been presented.