This Review will focus on four xenobiotic classes (PFAS, pesticides, PAHs, and PPCPs, Figure 1) and succinctly describe (1) the contextual background and chemical origin of each class, (2) the historically referenced methods for characterizing each group with a particular focus on those published from the U.S. Environmental Protection Agency (US EPA, Table 1), and (3) novel research methods for analyte extraction, separation, and detection published in the literature over the past two years (2018−2020). In general, the recent publications demonstrate either: (1) a targeted analysis approach for a predefined chemical class using a novel extraction procedure or an analytical method to enhance the selectivity or duty cycle or (2) an untargeted approach to characterize both known and unknown xenobiotics using high resolution MS instrumentation. Thus, the framework of this Review is broken down into these sections. While the selection of xenobiotic classes and cited references detailed in this Review are by no means inclusive of all current research efforts, our focus is to guide the reader toward a contextual framework of current environmental research and showcase future directions and applications.