Recent advancements in analytical chemistry and data analyses via high-resolution mass spectrometry (HRMS) are evolving scientific understanding of the potential totality of organic chemical exposure and pollutant risk. This review addresses the importance of HRMS approaches, namely suspect screening and nontarget chemical analyses, to the realm of phytoremediation. These analytical approaches are not without caveats and constraints, but they provide an opportunity to understand in greater totality how plant-based technologies contribute, mitigate, and reduce organic chemical exposure across scales of experimental and system-level studies. These analytical tools can enlighten the complexity and efficacy of plant-contaminant system design and expand our understanding of biogenic and anthropogenic chemicals at work in phytoremediation systems. Advances in data analytics from biological sciences, such as metabolomics, are crucial to HRMS analysis. This review provides an overview of targeted, suspect screening, and nontarget HRMS approaches, summarizes the expanding knowledge of regulated and unregulated organic chemicals in the environment, addresses requisite HRMS instrumentation, analysis cost, uncertainty, and data processing techniques, and offers potential bridges of HRMS analyses to phytoremediation research and application.