High-resolution mass spectrometry (HRMS) is a key technology for human exposomics, enabling the broad profiling of chemical exposure agents and related biomolecules. This review discusses the state-of-the-art HRMS-based technologies, current analytical workflows, and informatic pipelines for exposomic research. It highlights the need for new analytical and computational infrastructures to expand chemical space coverage, including gas/liquid chromatography–HRMS (GC-HRMS and LC-HRMS), and strategies to advance the field of the exposome. The exposome encompasses non-genetic exposures and includes environmental chemicals, transformation products, and biomolecules indicative of toxicological effects. HRMS allows for non-targeted analysis, which is increasingly used to identify environmental drivers of disease. Challenges include the diverse chemical space encompassing a wide dynamic range of exogenous chemicals and their transformation products in the human body at substantially lower levels than endogenous biomolecules. The review emphasizes the importance of harmonizing research efforts and benchmarking emerging toolkits essential for expanding the analytical coverage of exposomics. It also discusses the challenges and opportunities in advancing HRMS-based exposomics, aiming to provide a reference for chemists, toxicologists, epidemiologists, and stakeholders in health sciences. The article highlights the need for improved detection and annotation methods, as well as the integration of complementary techniques to reduce profiling biases and expand analytical coverage. It also discusses the importance of ion mobility spectrometry (IMS) in HRMS-based exposomics, which provides additional separation capabilities and helps in the identification of compounds. The review concludes with the need for further research and collaboration to advance the field of the exposome and improve health-oriented inferences.High-resolution mass spectrometry (HRMS) is a key technology for human exposomics, enabling the broad profiling of chemical exposure agents and related biomolecules. This review discusses the state-of-the-art HRMS-based technologies, current analytical workflows, and informatic pipelines for exposomic research. It highlights the need for new analytical and computational infrastructures to expand chemical space coverage, including gas/liquid chromatography–HRMS (GC-HRMS and LC-HRMS), and strategies to advance the field of the exposome. The exposome encompasses non-genetic exposures and includes environmental chemicals, transformation products, and biomolecules indicative of toxicological effects. HRMS allows for non-targeted analysis, which is increasingly used to identify environmental drivers of disease. Challenges include the diverse chemical space encompassing a wide dynamic range of exogenous chemicals and their transformation products in the human body at substantially lower levels than endogenous biomolecules. The review emphasizes the importance of harmonizing research efforts and benchmarking emerging toolkits essential for expanding the analytical coverage of exposomics. It also discusses the challenges and opportunities in advancing HRMS-based exposomics, aiming to provide a reference for chemists, toxicologists, epidemiologists, and stakeholders in health sciences. The article highlights the need for improved detection and annotation methods, as well as the integration of complementary techniques to reduce profiling biases and expand analytical coverage. It also discusses the importance of ion mobility spectrometry (IMS) in HRMS-based exposomics, which provides additional separation capabilities and helps in the identification of compounds. The review concludes with the need for further research and collaboration to advance the field of the exposome and improve health-oriented inferences.