American Indian and Alaska Native (AIAN) people’s health is often introduced as poor. The evidence shows that AIAN people are the most affected population in the United States (U.S.) with high rates of heart disease, diabetes, obesity, and many others. However, poor health does not occur in silo but is instead associated with an array of social determinants of health (SDOH) factors. These factors include government actions to natural environmental issues. One factor that is often mentioned today is the contribution of the genome to human health among Indigenous populations. The expectation from researchers and other actors is that participants in genomic research consent to the broad use of their DNA or that the resulting data is shared. These are immediate concerns for Tribal Nations based on past genomic research harms and power imbalances. Tribes can question how, when, and if they decide to engage in genomic research. It is the sovereign right of Tribes to determine whether to engage in genomic research, what makes the research equitable, how it benefits them, and whether to share the data. One aspect of genomic research often overlooked is the Traditional or cultural perspective about human genome research and whether it is acceptable. The future of genomics is complex, but with the training of new Indigenous scholars, there are ways to ensure that genomic research is culturally safe and respects Tribal sovereignty.