Dr. Yanyan Zhang was invited to deliver a talk on "Structure-dependent defluorination mechanisms of PFAS by advanced oxidation and reduction" at the CEE Seminar Series of Rice University.Developing complete defluorination technologies and designing readily degradable alternatives are the sustainable solution to address the global crisis of per- and polyfluoroalkyl substances (PFAS). This requires the following key questions to be answered: what structures can be degraded, to what extent, and why? Herein, we integrate density functional theory calculations with experimental kinetics to unravel the defluorination mechanism of diverse PFAS during advanced oxidation and reduction processes. We found that a single oxidizable moiety, including −CO2−, −CH or −CH2−, C=C, and −CON− or −SO2N−, in PFAS structures can enable their complete defluorination in sulfate radical-based systems. This proof-of-concept demonstrates that most of the diverse, complex PFAS structures encountered at discharging points and in spent media from phase-transfer technologies, can be destructed using simple oxidation approaches. Then, we proposed and validated an electron transfer-limiting mechanism for PFAS degradation by hydrated electrons, a critical technique for compounds lacking oxidizable moieties (e.g., perfluoroalkyl sulfonates). This theoretical framework unravels the long-standing mystery underlying the structure-dependent reactivity of PFAS with hydrated electrons and identifies functional moieties that favor electron transfer and thus defluorination, enabling the design of rapidly degradable alternatives. Our findings elucidate structure-dependent degradation mechanisms of PFAS at the molecular level and promote transformative solutions for sustainable practices in fluorine-intensive industries.