Since the early 20th Century, epidemiological research has brought benefits and burdens to Aboriginal communities in Canada. Many First Nations, Métis, and Inuit continue to view Western research with distrust; quantitative methods are perceived as especially inconsistent with indigenous ways of knowing. There is increasing recognition, however, that rigorous epidemiological research can produce evidence that draws attention and resources to pressing health issues in Aboriginal communities. We present a framework for culturally safe epidemiology, from the identification of research priorities, through fieldwork and analysis, to communication and use of evidence. Modern epidemiology and indigenous knowledge are not inherently discordant; many public health opportunities arise at this interface and good science must begin here too.