People are living longer because of advances made through biomedical research. The challenge in genetic research on indigenous peoples is that it raises a complex range of legal, ethical, social, spiritual, and political issues. The current research paradigm is one of paternalism and biocolonialism. Such was the case of the Havasupai, who believed their blood samples were to be solely used for their collective benefit and well-being, and Native Hawaiians, who are opposed to genetically modified taro. Pertinent questions that should be considered before conducting research with and amongst Native communities include: Is there informed consent or the need for re-consent? Is cultural knowledge respected? Are indigenous beliefs, values, and practices taken into account? Is there potential for group harm? Is there accountability to community? Establishing a community Institutional Review Board may be the most effective means toward achieving equal and ethical treatment in population/group-based research. Research should be about ethically rigorous processes and effectively tailored interventions that address community needs, interests, and values.