Substance abuse has been an intractable societal concern in the US for more than half a century. The recent opioid epidemic has only accentuated this problem. Adolescents are significant long-term contributors to the crisis due to their susceptibilities to drug abuse and impressionable age. This review examines the particular vulnerabilities of the adolescent brain to drug abuse and the risk and protective factors thereof, especially in light of the Rat Park studies. In addition, the article provides an overview of the evidence-based prevention program registries and offers detailed summaries of two: Blueprints for Healthy Youth Development (Blueprints) and the Washington State Institute for Public Policy (WSIPP). By combining inputs from Blueprints and WSIPP, five programs with the highest benefit-cost ratios (BCR) were identified: Functional Family Therapy, Positive Family Support, Lifeskills Training, Positive Action, and Good Behavior Game. In light of their outstanding characteristics, these programs are poised to be widely implemented and to make a measurable difference in the fight against substance and opioid abuse.