Adolescent substance use and its resulting harms are major concerns of parents, youth-serving professionals, policymakers, private philanthropies, and public health officials. Numerous prevention initiatives have been launched, yet use rates for cigarettes, marijuana, and other illicit drugs have risen during the last decade [1]. This paper argues that current prevention approaches could be improved by enlisting and providing tools to institutions that regularly serve children and youth. The role of these institutions would be to systematically identify children at high risk and to provide them with, or refer them to, appropriate prevention services. Institutions selected for consideration in this discussion include primary health care facilities and schools. Early identification of at-risk youth is not a new concept, but it is one that has proven extraordinarily difficult to implement in institutional settings [2]. For scientists and practitioners, the goal of alcohol, tobacco, and other drug (ATOD) prevention is the avoidance of shortand long-term consequences related to substance abuse and addiction. To achieve this goal, programs can use a “universal” prevention approach, targeting the general population; a “selective” approach, targeting subgroups at risk; or an “indicated” approach, targeting persons who are already experimenting with drugs or who exhibit other risk-related behaviors [3–5]. Universal prevention approaches are most commonly used and include public awareness campaigns and school health curricula about substance abuse. This article, however, focuses on selective and indicated approaches to systematically identify and target more intensive ATOD prevention services for children and youth at highest risk of harm. Recent research provides detailed information about risk indicators and their use in identifying at-risk children and preventing future problems from ATOD use [6,7]. This review begins with evidence about specific risk factors that predict substance abuse and addiction and how these risks or behaviors might be detected by institutions. Next, we will review how each system currently participates in early identification and prevention activities, the barriers that have limited the development of effective substance abuse screening and prevention programs, and examples of promising and effective programs. Finally, the authors provide recommendations for strengthening the role of health care systems and schools in prevention.