Social determinants of health and their effects on health outcomes create a complex system, with interaction between social, economic, physical, and biological factors necessitating research take a holistic approach. Transdisciplinary research, one of the three core values of the Collaborative Research Center for American Indian Health, seeks to go beyond methods of knowledge production occurring solely within disciplinary boundaries, because real-world societal problems do not adhere to such restrictions. Community involvement is an essential component for successful research partnerships with American Indian and Alaska Native (AI/AN) communities. We posit that transdisciplinary approaches, which considers community-level expertise as an equitable component on the research team, show great potential for advancing research in AI/AN communities.