Under the exposome paradigm all nongenetic factors contributing to disease are considered to be ‘environmental’ including chemicals, drugs, infectious agents, and psychosocial stress. We can consider these collectively as environmental stressors. Exposomics is the comprehensive analysis of exposure to all environmental stressors and should yield a more thorough understanding of chronic disease development. We can operationalize exposomics by studying all the small molecules in the body and their influence on biological pathways that lead to impaired health. Here, we describe methods by which this may be achieved and discuss the application of exposomics to cumulative risk assessment in vulnerable populations. Since the goal of cumulative risk assessment is to analyze, characterize, and quantify the combined risks to health from exposures to multiple agents or stressors, it seems that exposomics is perfectly poised to advance this important area of environmental health science. We should therefore support development of tools for exposomic analysis and begin to engage impacted communities in participatory exposome research. A first step may be to apply exposomics to vulnerable populations already studied by more conventional cumulative risk approaches. We further propose that recent migrants, low socioeconomic groups with high environmental chemical exposures, and pregnant women should be high priority populations for study by exposomics. Moreover, exposomics allows us to study interactions between chronic stress and environmental chemicals that disrupt stress response pathways (i.e., ‘stressogens’). Exploring the impact of early life exposures and maternal stress may be an interesting and accessible topic for investigation by exposomics using biobanked samples. Environ. Mol. Mutagen. 56:715–723, 2015. © 2015 Wiley Periodicals, Inc.