Per- and polyfluoroalkyl substances (PFAS) are often called ‘forever chemicals’. This colloquialism reflects that many PFAS are recalcitrant to environmental and metabolic degradation, leading to long environmental and biological half-lives. This persistence, a concerning characteristic of these synthetic substances, is also a reason they are used in many products and processes. Most PFAS have physical−chemical properties that enable them to withstand extreme conditions and make them useful for a range of applications, including as surfactants or coatings that confer oil-, stain- and water-repellency. This combination of persistence and wide use has resulted in extensive environmental contamination and the presence of PFAS in living organisms, leading to use restrictions. Increasing evidence of health effects has also led to implementation of health protective guidelines. In the United States, federal regulations enacted in 2024 limit levels of six PFAS in drinking water; in the European Union, a proposed restriction would control use, import and production of the vast majority of PFAS. This Perspective article summarizes how knowledge of toxicological hazards and health-related costs of PFAS has progressed in recent years, leading to actions to restrict PFAS uses.