The misuse of prescription drugs by teens in the United States is a growing public health problem. This article provides a systematic synthesis of multiple strands of literature to recommend effective prevention methods. Using a social-ecological framework, we review the scope of the problem of prescription drug use among teens. Then, we analyze the multiple factors that may influence teen knowledge and attitudes toward prescription drugs and discuss the important challenges related to the construction of effective prevention programs. Finally, we provide recommendations for practice that attempt to overcome these challenges.