Per- and polyfluoroalkyl substances (PFASs) are synthetically manufactured chemicals used in commercial products (e.g. food packaging, flame retardants) as well as in industrial applications. An increase in the incidence of adverse health effects has been reported with the continued use and exposure to PFASs such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). These “forever chemicals” persist in our environment, and when ingested they accumulate in our bodies. PFAS exposure has been found to influence human health and may contribute to cardiovascular disease, immune dysfunction, and several cancers. Here we use whole genome CRISPR screening to investigate how PFAS exerts its toxic activities on human cells. Top gene hits from screen results identified genes involved in ROS production, apoptosis and cellular senescence. We continue to investigate the mechanisms of action for PFAS and this information may guide the development of targeted therapeutics for PFOS poisoning.