Health-based guidance values (HBGV) based on toxicological endpoints are used in the conventional process for setting water quality guidelines protective of human health. In the case of polyfluoroalkyl substances (PFAS) these values have been steadily decreasing over the past decade, with consequent reductions in water quality guideline values set by jurisdictions at different times. There are a number of reasons for this. Toxicological endpoints derived from controlled exposure studies in animals have differed, the adjustments made to convert experimental doses to human-equivalent doses have differed, as has the choice of uncertainty factors applied in the process. More recently, human data derived from epidemiological studies have been used as a starting point for the HBGV process, although some doubt remains as to the suitability of these data. Among the PFAS congeners, most of the useful toxicological data relates to the 8-carbon straight-chain compounds PFOS and PFOA, with HBGV for the 6-carbon PFHxS usually combined with PFOS, assuming additivity in their toxicological profiles. Because of this lack of useful toxicological data, established water quality guidelines generally cover only a few PFAS. Also, Toxicity Equivalence Factors (TEF) have not been well established to guide the risk assessment of complex mixtures of PFAS. The implications of these data gaps and ways to address them need to be addressed.