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This paper examines the overlaps and tensions that exist between international human rights law protecting indigenous peoples and international investment and trade regimes. Significant progress has been made in recent decades toward the recognition and protection of the rights of indigenous peoples in international human rights law. Latin American countries have been particularly active in this area, ratifying the International Labor Organization’s Indigenous and Tribal Peoples Convention (C 169) and the United Nations Declaration on the Rights of Indigenous Peoples. Yet, at the same time, many of these countries have joined international economic regimes that have sometimes been at odds with their international and domestic commitments on indigenous rights. To illustrate these tensions, I use evidence from three contentious cases of investor-indigenous conflicts that have resulted in complex disputes between Latin American governments and multinational firms in international arbitration tribunals. The case studies show how not only states but also civil society and private sector actors take advantage of overlaps between domestic, regional and international institutions to promote their interests. The paper also highlights the relative weakness of human rights agreements vis-à-vis international economic regimes, and discusses several alternatives to address these asymmetries.