Non-targeted analysis (NTA) and suspect screening analysis (SSA) are powerful techniques that rely on high-resolution mass spectrometry (HRMS) and computational tools to detect and identify unknown or suspected chemicals in the exposome. Fully understanding the chemical exposome requires characterization of both environmental media and human specimens. As such, we conducted a review to examine the use of different NTA and SSA methods in various exposure media and human samples, including the results and chemicals detected. The literature review was conducted by searching literature databases, such as PubMed and Web of Science, for keywords, such as “non-targeted analysis”, “suspect screening analysis” and the exposure media. Sources of human exposure to environmental chemicals discussed in this review include water, air, soil/sediment, dust, and food and consumer products. The use of NTA for exposure discovery in human biospecimen is also reviewed. The chemical space that has been captured using NTA varies by media analyzed and analytical platform. In each media the chemicals that were frequently detected using NTA were: per- and polyfluoroalkyl substances (PFAS) and pharmaceuticals in water, pesticides and polyaromatic hydrocarbons (PAHs) in soil and sediment, volatile and semi-volatile organic compounds in air, flame retardants in dust, plasticizers in consumer products, and plasticizers, pesticides, and halogenated compounds in human samples. Some studies reviewed herein used both liquid chromatography (LC) and gas chromatography (GC) HRMS to increase the detected chemical space (16%); however, the majority (51%) only used LC-HRMS and fewer used GC-HRMS (32%). Finally, we identify knowledge and technology gaps that must be overcome to fully assess potential chemical exposures using NTA. Understanding the chemical space is essential to identifying and prioritizing gaps in our understanding of exposure sources and prior exposures.Impact statement: This review examines the results and chemicals detected by analyzing exposure media and human samples using high-resolution mass spectrometry based non-targeted analysis (NTA) and suspect screening analysis (SSA).