Stress and trauma can compromise physical and mental health. Rural Alaska Native communities have voiced concern about stressful and traumatic events and their effects on health. The goal of the Yup’ik Experiences of Stress and Coping Project is to develop an in-depth understanding of experiences of stress and ways of coping in Yup’ik communities. The long-range goal is to use project findings to develop and implement a community-informed and culturally grounded intervention to reduce stress and promote physical and mental health in rural Alaska Native communities. This paper introduces a long-standing partnership between the Yukon-Kuskokwim Regional Health Corporation, rural communities it serves, and the Center for Alaska Native Health Research at the University of Alaska Fairbanks. Within the context of the Stress and Coping project, we then discuss the value and challenges of taking a CBPR approach to advance science and address a priority community concern, and share strategies to respond to challenges. Focus groups were conducted to culturally adapt an existing structured interview and daily diary protocol to better fit Yup’ik ways of knowing. As modified, these interviews increased understanding of stress and coping particular to two Yup’ik communities. Challenges included the geographical nature of Yup’ik communities, communication barriers, competing priorities, and confidentiality issues. Community participation was central in the development of the study protocol, helped ensure that the research was culturally appropriate and relevant to the community, and facilitated access to participant knowledge and rich data to inform intervention development.