Progress in identifying effective programs and policies for preventing tobacco, alcohol, and illicit drug use has stimulated a growing sense of optimism about the potential of prevention science and practice. This paper summarizes some of the key challenges and critical issues that still need to be addressed for the advances of the past two decades of prevention research to have an impact on the nature of prevention practice and eventually translate into reductions in mortality and morbidity. In addition to identifying effective strategies for disseminating the use of evidence-based prevention programs and policies, issues related to implementation fidelity and adaptation need to be better understood as well as factors associated with institutionalization of effective prevention programs. Further advances in prevention science and practice will require a new emphasis on blended research models that involve conducting prevention research in practice settings with the active collaboration of researchers and practitioners.