Ether-based PFAS such as HFPO-DA (GenX), ADONA, and chlorinated PFESAs (F-53B) have replaced legacy PFOS and PFOA but remain environmentally persistent and biologically recalcitrant. Their ether linkages, electron-withdrawing headgroups, and perfluorinated backbones hinder enzymatic access and CF bond cleavage. Current evidence indicates slow oxidative modification for GenX, while ADONA remains largely resistant and undergoes only chemical (total oxidizable precursor (TOP)-like) oxidation to PFMOPrA; F-53B is subject to reductive dechlorination to 6:2H-PFESA without defluorination. This review synthesizes molecular-to-process-level insights on bioremediation of ether-PFAS substitutes, consolidating recent data from microbial, fungal, enzymatic, and plant systems. A clear structure-reactivity rule was identified: α-C-H/α-CHF or CCl "handles" facilitate transformation, whereas full fluorination and steric shielding enforce persistence. Because intrinsic biological turnover is slow, hybrid treatment trains that combine physicochemical pre-activation (UV/sulfite, electro-Fenton, plasma, or vitamin B12/sulfide reduction) with aerobic or rhizospheric bio-polishing offer a credible route to partial mineralization (≈10-30% defluorination). Emerging genetically enhanced systems: engineered microbes expressing oxygenases, dehalogenases, or fluoride-export modules, and transgenic plants harboring oxidative enzymes, represent the next frontier for bridging chemical activation and biological degradation. A technology-readiness matrix ranks feasible chemo-bio scenarios across water, sludge, and soil environments. This review outlines a research agenda that integrates enzyme design, synthetic biology chassis optimization, and structure-guided modeling to predict degradability. Embedding molecular persistence into regulatory assessment is essential to prevent future "regrettable replacements."