Environmental exposures to exogenous chemicals throughout the lifespan of individuals have been widely recognized as significant contributors to numerous diseases. Therefore, acquiring a comprehensive understanding of the exposome is crucial in identifying sources of exposure and developing strategies to prevent or mitigate such exposures. Consequently, these efforts can lead to a reduction in associated health risks. Recent advancements in analytical technologies such as high-resolution mass spectrometry (HRMS) and nontargeted analysis have emerged as valuable tools for covering and screening a broader chemical space. Consequently, this chapter covers the principles and techniques of HRMS in exposome research. It provides examples of studies that have employed HRMS to identify potential risk factors within pregnancy cohorts, which serve as a particularly interesting case in human biomonitoring investigations. Furthermore, this chapter addresses other pertinent aspects, including instrumentation, sample preparation and data acquisition, processing, management, and prioritization. Lastly, the chapter presents an overview of potential future applications of HRMS in exposome research, alongside a summary of its current state-of-the-art capabilities.