This article presents comparative perspectives from Australia, the European Union, and the United States from a plenary session, “Herbicide resistance: Challenges for farmers and implications for the environment” at the 19th Annual Conference of the International Consortium on Applied Bioeconomy Research. Herbicide resistant (HR) crops offer improved weed control, reduced soil erosion and fossil fuel use from tillage, and substitution toward herbicides less toxic or persistent in the environment. Widespread HR crop adoption, however, has reduced the diversity of weed control tactics, leading to a dramatic rise of HR weeds. HR weeds threaten the sustainability of HR crops, pose environmental risks from alternative herbicide treatments, and are altering public and private R&D programs. Institutional responses to HR weeds, while confronting similar problems (in some respects, but not others) are taking different forms across the three regions. The article discusses public policies and private sector strategies to address weed resistance problems. Considerations of HR weeds are already transforming regulatory approval processes for new HR crop varieties. We conclude by discussing over-arching public policy and agricultural research challenges.