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To better tackle diseases and sustain healthy ecosystems, One Health programs must efficiently bridge health in humans, domestic/livestock species, wild animals and plants, agriculture/aquaculture, and the environment. The Smithsonian Institution proposes to address this by considering 'health' in a broad sense - the absence of undue pathogens and unnecessary stress for any organisms as well as access to good living conditions in functional environments. Considering the interconnectedness of all life forms, the Smithsonian plans to create a framework that will integrate cultural, social, and educational components into health research on humans, animals, plants, or ecosystems. The objectives of this perspective article are to (1) propose an innovative framework to support an interconnected/integrated approach to health and (2) provide examples fostering impactful collaborations on One Health research and education. Based on the core strengths of the Smithsonian (multidisciplinary research, outreach and education programs, libraries/archives, and collections) and central institutional support, this framework has the potential to extend existing health-related projects, address new needs and situations (e.g., response to pandemics), provide invaluable resources to inform policy and decision makers, and educate all audiences globally., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Comizzoli, Pagenkopp Lohan, Muletz-Wolz, Hassell and Coyle.)