Alternatives assessment is a methodology used to identify, evaluate, and compare potential chemical and nonchemical solutions with a substance of concern. It is required in several chemicals management regulatory frameworks, with the objective of supporting the transition to safer chemistry and avoiding regrettable substitutions. Using expert input from symposium presentations and a discussion group hosted by the Association for the Advancement of Alternatives Assessment, four case examples of the use of alternatives assessment in regulatory frameworks were evaluated and compared: (1) the US Environmental Protection Agency Significant New Alternatives Policy (USEPA SNAP), (2) authorization provisions in the EU REACH (Registration, Evaluation, Authorisation, and Restriction of Chemicals) regulation, (3) the California (CA) Safer Consumer Products (SCP) Program, and (4) the Safer Products for Washington (WA) Program. Factors such as the purpose of the alternatives assessment, the timeline of actions, who completes the assessment, the role of stakeholder engagement, and the regulatory response options for each policy are outlined. Through these presentations and expert discussions, four lessons learned about the use of alternatives assessments in regulatory policy emerged: (1) the goal and purpose of the regulatory framework significantly affects its ability to result in safer substitution, (2) existing frameworks struggle with data access and insufficient stakeholder engagement, (3) some frameworks lack clear decision rules regarding what is a safer and feasible alternative, and (4) regulatory response options provide limited authority for enforcement and do not adequately address options where alternatives are unavailable or limited. Five recommendations address these lessons as well as how the application of alternatives assessment in regulatory settings could have greater impact in the future. This synthesis is not meant to be a comprehensive policy analysis, but rather an assessment based on the perspectives from experts in the field, which should be supplemented by formal policy analysis as policies are implemented over time.