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American Indians and Alaska Natives (AI/ANs) suffer a disproportionate burden of diabetes and kidney failure. For those with chronic kidney disease, transplantation may be the most effective treatment option. However, low rates of organ donation and transplantation are reported for AI/ANs, who face significant barriers in accessing the transplant waiting list. They are also less likely than Whites to consent to become organ donors. We partnered with five tribal colleges and universities to conduct focus groups to assess knowledge, cultural beliefs, and behaviors related to organ donation and transplantation among AI/AN college students. Focus group data were used to develop a culturally targeted media campaign and outreach strategy aimed at increasing rates of consent to donate organs. Community knowledge typically drew from direct family experience with chronic illness. Study findings confirmed that attitudes about organ donation were influenced by cultural beliefs. Nevertheless, many participants supported organ donation even when it conflicted with cultural and spiritual beliefs about keeping the body intact for burial. Participants also expressed mistrust of the local health care system, suggesting that trust issues might interfere with health messaging on this topic. This is the first study to examine sociocultural beliefs about organ donation among AI/AN college students. Through focus group findings, study staff were better positioned to develop culturally relevant outreach materials. Rising rates of chronic illness among AI/ANs ensure that organ donation and transplantation will be a long-term feature of the health landscape in AI/AN communities. Targeted health messaging must be part of the strategy to reduce donor shortages.