International policy discussions on plastic pollution are entering a new phase, with more than 100 governments calling for the launch of negotiations for a new global plastics agreement in 2022. This article aims to contribute to efforts to identify effective international policy levers to address plastic pollution. It takes stock of the evolution of views and perceptions on this complex and multi-faceted topic—from concerns about marine pollution and waste management towards new strategic directions that involve the entire plastics life-cycle and include climate and health impacts associated with the proliferation of plastics. It also traces the progressive development of responses—from voluntary approaches invovling multiple stakeholders to national and international approaches focused on regulation. The paper is informed by desk research, a literature review and participation by the authors in informal and formal global governance processes on plastic pollution, the environment and development in the United Nations and World Trade Organization between 2019 and 2021. It also draws on empirical findings from a novel and original database on the life-cycle of plastic trade created by the authors. The paper argues that the important focus on downstream dimensions of plastic pollution—and strategies to address them—needs to be complemented by a broad life-cycle and “upstream” perspective that addresses plastic pollution at its source. It highlights the political economy tensions and inconsistencies at hand, observing that while some countries are taking concerted efforts to reduce pollution (including through bans on certain kinds of plastic and plastic products); to promote more circular plastic economies; and to reduce the carbon footprint of plastics (as part of a wider effort to decarbonize their economies), trade and investment in the plastic industry continues to rise. The paper argues that to reduce plastic pollution, emerging global governance efforts must integrate international environmental law and cooperation with a complementary and enabling global framework that addresses the economic, financial, industrial and trade policies needed to drive the necessary transformation of the plastics sector.