This article reviews the international legal framework on hazardous substances, with an emphasis on the Arctic and the roles of indigenous peoples. Persistent organic pollutants (POPs) and heavy metals pose significant risks to Arctic indigenous populations, mainly through the consumption of traditional foods. Treaties of particular relevance include the Protocols on Heavy Metals and POPs to the Convention on Long-Range Transboundary Air Pollution (1998) and the Stockholm Convention on POPs (2001). Arctic indigenous groups have exerted considerable influence on hazardous substance management through lobbying of national governments, participation in domestic and international scientific assessments, and direct advocacy in regional and global political fora. Their engagement on environmental issues has also helped to shape circumpolar consciousness and political activism among different indigenous groups. At the same time, there remain important limitations on the independent authority and ability to act of indigenous groups. Challenges for Arctic indigenous groups and States include continuing collaborative abatement work targeting many POPs and heavy metals, as well as addressing linkages between hazardous substances and climate change, which is another issue of great Arctic concern.