The article by Lawrence P. Wackett challenges the conventional view that the persistence of per- and polyfluorinated compounds (PFAS) in the environment is primarily due to the strength of the C–F bond. Instead, Wackett argues that the low biodegradability of PFAS is better understood as a biological optimization problem driven by evolution. He highlights recent findings that show PFAS can be enzymatically degraded by microorganisms, particularly through the use of known C–F cleaving systems. Wackett emphasizes that the environmental persistence of PFAS is not due to chemical resistance but rather the evolutionary insufficiency of current microbial systems to degrade these compounds. He suggests that the biological and chemical examples of enzymatic defluorination of PFAS indicate that C–F bonds in many commercial PFAS are susceptible to enzymatic attack. The article also discusses the challenges and energy costs associated with biodegrading highly fluorinated compounds, such as the production of toxic fluoride anions, which impose strong negative selection against biodegradation. Wackett concludes that the persistence of PFAS is best explained by evolutionary factors rather than chemical ones, and he calls for a shift in approach to focus on directed evolution of biological systems containing known C–F cleaving systems.The article by Lawrence P. Wackett challenges the conventional view that the persistence of per- and polyfluorinated compounds (PFAS) in the environment is primarily due to the strength of the C–F bond. Instead, Wackett argues that the low biodegradability of PFAS is better understood as a biological optimization problem driven by evolution. He highlights recent findings that show PFAS can be enzymatically degraded by microorganisms, particularly through the use of known C–F cleaving systems. Wackett emphasizes that the environmental persistence of PFAS is not due to chemical resistance but rather the evolutionary insufficiency of current microbial systems to degrade these compounds. He suggests that the biological and chemical examples of enzymatic defluorination of PFAS indicate that C–F bonds in many commercial PFAS are susceptible to enzymatic attack. The article also discusses the challenges and energy costs associated with biodegrading highly fluorinated compounds, such as the production of toxic fluoride anions, which impose strong negative selection against biodegradation. Wackett concludes that the persistence of PFAS is best explained by evolutionary factors rather than chemical ones, and he calls for a shift in approach to focus on directed evolution of biological systems containing known C–F cleaving systems.