The introduction into the Baltic Sea of hazardous substances that are persistent, bioaccumulate, and are toxic is an important environmental and human health problem. Multilateral efforts to address this problem have primarily been taken under the Helsinki Commission (HELCOM). This article examines past HELCOM efforts on hazardous substances, and discusses future challenges regarding their management. The article finds that past actions on hazardous substances have had a positive effect on improving Baltic environmental quality and reducing human health risks, although there are remaining issues and difficulties that need to be addressed. In particular, four related future challenges for HELCOM management of hazardous substances are identified and discussed: i) the need to engender further implementation and building public and private sector capacities; ii) the need to improve data availability, quality and comparability across the region and international fora; iii) the need to strengthen existing regulations and incorporate new issues; and iv) the need to effectively coordinate HELCOM activities with efforts on hazardous substances in other international fora.