Per- and polyfluoroalkyl substances (PFAS) are in 99% of humans and are associated with a range of adverse health outcomes. It is impossible to test the >
14,500 structurally diverse "forever chemicals" for safety, therefore improved assays to quantify structure-activity relationships are needed. Here, we determined the toxicity of a structurally distinct set of PFAS in twelve genetically diverse strains of the genetic model system Caenorhabditis elegans. Dose-response curves for perfluoroalkyl carboxylic acids (PFNA, PFOA, PFPeA, and PFBA), perfluoroalkyl sulfonic acids (PFOS and PFBS), perfluoroalkyl sulfonamides (PFOSA and PFBSA), fluoroether carboxylic acids (GenX and PFMOAA), fluoroether sulfonic acid (PFEESA), and fluorotelomers (6:2 FTCA and 6:2 FTS) were determined in the C. elegans laboratory reference strain, N2, and eleven genetically diverse wild strains. Body length was quantified after 48 hr of developmental exposure of L1 arrest-synchronized larvae to estimate effective concentration values (EC50). PFAS toxicity ranged by three orders of magnitude. Long-chain PFAS had greater toxicity than short-chain and fluorosulfonamides were more toxic than carboxylic and sulfonic acids. Genetic variation resulted in variation in susceptibility among twelve strains to almost all chemicals. Different C. elegans strains varied in susceptibility to different PFAS, which suggests distinct molecular responses to specific structural attributes. Harnessing the natural genetic diversity of C. elegans and the structural complexity of PFAS is a powerful approach that can be used to investigate mechanisms of toxicity which may identify potentially susceptible individuals or populations and predict toxicity of untested PFAS to inform regulatory policies and improve human and environmental health.