Exceptional properties at the nano-scale, if appropriately harnessed, will lead to innovations in water treatment. Nanomaterials can enable treatment processes with accelerated reaction kinetics, self-healing or self-regeneration abilities, and a high degree of selectivity for targeted pollutant removal. These materials can also introduce new pathways for the removal of contaminants that are challenging to degrade employing traditional techniques. One such class of contaminants is poly- and per-fluoroalkyl substances (PFAS), which are widely detected in waterways of the U.S. and drinking water supplies. The U.S. Environmental Protection Agency (EPA) has listed two PFAS (i.e., perfluorooctanesulfonic acid or PFOS and perfluorooctanoic acid or PFOA) in the Contaminant Candidate List and recently has revised the lifetime health advisories. PFAS molecules are persistent in the environment over long periods because they are not photolyzed or biodegraded. Current mitigation technologies mostly depend on non-destructive phase transfer processes (e.g., adsorption, filtration, or ion exchange) which results in a concentrated waste stream. Few destructive mitigation methods transform PFAS by cleaving C–C bonds but it is not clear if the transformation products (e.g., shorter chain PFAS) are less toxic or less persistent. Thus, the central challenge for PFAS transformation lies in cleaving the strong C–F bonds. Nanomaterials can enable treatment options by providing high-energy reaction pathways; e.g., electrolysis, thermolysis, or photolysis. This perspective aims to present a critical review on reported PFAS removal/destruction techniques, provide molecular-level insights into possible removal/destruction pathways, and propose potential nano-enabled remediation options for these persistent contaminants.