Indigenous peoples are the descendants of the original inhabitants of lands that have been subject to the destructive force of European colonization. The relationship between Indigenous peoples and settlers in North America has been strained by centuries of colonial violence, racism, and systemic discrimination in policy and practice. One of the primary barriers that continue to impede progress, is a lack of understanding of these oppressive systems and their ongoing impact on Indigenous peoples today. In an effort to inform clinicians and researchers who may interact with Indigenous peoples and their communities, this chapter will (a) explore historic and ongoing injustices perpetrated against Indigenous peoples; (b) provide examples of harms done in the name of science, medicine, and social work; (c) discuss the processes of decolonization and self-determination in research and clinical practice, and (d) suggest individual and group behaviors which may lead to progress in the form of respectful partnerships.