Background: Translation science entails application of information gained through scientific research to practices intended to improve prevention and public health. The outreach arm of Land-Grant Universities--the Cooperative Extension System--is uniquely poised to facilitate this translation process and contribute to resolution of current substance misuse and other behavioral health issues. Objective: This paper summarizes selected literatures that guided the conceptualization of a framework for building Extension's capacity to enhance the translation process, in order to better address substance misuse and other behavioral health issues. Method: Peer-reviewed literature was obtained from journals representing varied disciplines including medicine, public health, education, and psychology. Journals for Extension professionals were a prominent source of relevant literature. The literature review informed the identification of relevant practice gaps, barriers in addressing those gaps, and the development of a capacity-building framework. Results: The framework described highlights opportunities for building Cooperative Extension's capacity to address goals in four key domains. These goals include: (1) catalyzing Extension's organizational development to support science-driven practices; (2) bolstering prevention and behavioral health-oriented professional development for Extension faculty and staff; (3) creating a stronger culture of behavioral health in Extension; and (4) strengthening Extension's financing of prevention-oriented behavioral health efforts. Conclusion: Addressing the capacity-related goals identified in this paper could be a major catalyst for enhancing the power of proven, prevention-oriented behavioral health and, thereby, the well-being of our families, communities and nation.