The last decade has been characterized by an increasing focus on the question: "What works to promote and protect the health and well-being of adolescents?" This question is raised in multiple arenas, from pregnancy prevention to substance use and violence prevention, as well as for broad populations of young people. An accumulating body of evidence underscores the effectiveness of a dual strategy of enhancing protective factors and promoting healthy youth development while seeking to reduce risk factors in the lives of youth. Building upon research frameworks of the 1970s and 1980s that emphasized the concepts of resiliency, risk, vulnerability, and protective factors, this research provides insights into best practices when the weight of evidence is sufficiently developed, as well as ideas about "best bets" when strategies show particular promise. Critical to the ongoing advancement of adolescent health is a powerful, evidence-based response to the argument that "nothing can be done" for high-risk youth. This perspective must be superseded by practitioners, researchers, and advocates who demonstrate, at multiple points of intervention, that the dual approach of risk reduction and enhancement of protective factors constitutes an effective strategy for adolescent health promotion.