The article "High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage" by Yunjia Lai et al. reviews the advancements and challenges in using high-resolution mass spectrometry (HRMS) for profiling chemical exposure agents and related biomolecules in human exposomics. The exposome, which encompasses non-genetic exposures, is a critical link between genetic drivers and disease outcomes. HRMS, known for its high sensitivity, rapid data acquisition, and increased resolution of chemical space, has emerged as a leading technology for broad profiling of chemical exposures. However, HRMS-based exposomics faces unique challenges, including the need for new analytical and computational infrastructures to expand coverage through streamlined, scalable, and harmonized workflows. The article surveys state-of-the-art HRMS-based technologies, current analytical workflows, and informatic pipelines, providing a reference for chemists, toxicologists, epidemiologists, and stakeholders in health sciences. It highlights the need to benchmark fit-for-purpose platforms, such as gas/liquid chromatography–HRMS (GC-HRMS and LC-HRMS), to expand chemical space coverage. The authors discuss opportunities, challenges, and strategies to advance the field of exposomics, emphasizing the importance of harmonizing research efforts and benchmarking emerging toolkits. Key aspects covered include the definition of the human exposome in chemical space, the vast chemical space encompassing environmental chemicals and their transformation products, and the dynamic range of exposome chemicals. The article also delves into the experimental techniques and workflows, including sample matrices, pretreatment, pre-MS separation, and ionization methods. It discusses the advantages and limitations of different chromatographic techniques (GC and LC) and the emerging role of ion mobility spectrometry (IMS) in HRMS-based exposomics. Overall, the article aims to provide a comprehensive overview of the current state and future directions of HRMS-based exposomics, highlighting the need for interdisciplinary collaboration and technological advancements to fully realize the potential of this field in understanding and addressing environmental health issues.The article "High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage" by Yunjia Lai et al. reviews the advancements and challenges in using high-resolution mass spectrometry (HRMS) for profiling chemical exposure agents and related biomolecules in human exposomics. The exposome, which encompasses non-genetic exposures, is a critical link between genetic drivers and disease outcomes. HRMS, known for its high sensitivity, rapid data acquisition, and increased resolution of chemical space, has emerged as a leading technology for broad profiling of chemical exposures. However, HRMS-based exposomics faces unique challenges, including the need for new analytical and computational infrastructures to expand coverage through streamlined, scalable, and harmonized workflows. The article surveys state-of-the-art HRMS-based technologies, current analytical workflows, and informatic pipelines, providing a reference for chemists, toxicologists, epidemiologists, and stakeholders in health sciences. It highlights the need to benchmark fit-for-purpose platforms, such as gas/liquid chromatography–HRMS (GC-HRMS and LC-HRMS), to expand chemical space coverage. The authors discuss opportunities, challenges, and strategies to advance the field of exposomics, emphasizing the importance of harmonizing research efforts and benchmarking emerging toolkits. Key aspects covered include the definition of the human exposome in chemical space, the vast chemical space encompassing environmental chemicals and their transformation products, and the dynamic range of exposome chemicals. The article also delves into the experimental techniques and workflows, including sample matrices, pretreatment, pre-MS separation, and ionization methods. It discusses the advantages and limitations of different chromatographic techniques (GC and LC) and the emerging role of ion mobility spectrometry (IMS) in HRMS-based exposomics. Overall, the article aims to provide a comprehensive overview of the current state and future directions of HRMS-based exposomics, highlighting the need for interdisciplinary collaboration and technological advancements to fully realize the potential of this field in understanding and addressing environmental health issues.