Per- and polyfluoroalkyl substances (PFAS) are of increasing concern. In October 2021, the U.S. Environmental Protection Agency (EPA) announced an action plan for addressing PFAS, including establishing maximum contaminant levels for drinking water. The vast presence and detrimental impact to human health and the environment of these analytically challenging compounds has led to focus on technique rigor necessary for sensitive, reproduceable and reliable data. In this article, Senior Application Scientist, Jamie Foss, addresses the differences between EPA methods 533 and 537.1, and how to overcome key LC-MS/MS technique challenges when performing analysis in accordance with these methods.