The Berkeley Superfund Research Center, in consultation with the Program’s key stakeholders, has identified four complex problems associated with hazardous waste sites that have proven intractable to current methods. These problems are how to better assess: 1) cumulative impacts from multiple environmental stressors (e.g. chemical exposures, stress and obesity); 2) past exposures, especially early-life exposures and their contribution to risk; 3) the effects of chemical mixtures and their impact on remediation efforts; and, 4) the complex transformation of chemicals to reactive intermediates and their ability to act through multiple mechanistic pathways. Here we propose six interactive projects (4 biomedical and 2 engineering) and 5 cores that aim to address these four problems though original research, translation to appropriate end-users and community engagement efforts. We will focus on exposures to high priority chemicals commonly found at Superfund sites, including arsenic, benzene, trichloroethene, formaldehyde, chromium and polycyclic aromatic hydrocarbons to address the specific mandates of the Program. We will, however, take a novel approach in adopting the so-called ‘exposome paradigm’ in our research. This new paradigm, which we helped develop, allows for a ‘seeing the whole picture’ approach to risk assessment, hazard identification and the safe and effective remediation of hazardous sites containing multiple chemicals. In the exposome paradigm all nongenetic environmental stressors are considered as environmental exposures. Therefore, cumulative risk assessment, where the impact of all stressors on a population is assessed, could be operationalized by exposomics. Communities living near sites face cumulative risks from a variety of environmental and social factors. The theme of our Center is therefore the exposome and we propose a step-wise approach to applying exposomics to help solve the complex problems found at Superfund sites. Biomedical Projects 1-4 aim to develop advanced techniques for the detection, assessment, and evaluation of the effects and risk to human health of hazardous substances; Engineering Project 5 will develop methods to detect new hazardous substances in the environment and together with Engineering Project 6 will develop methods to reduce the amount and toxicity of hazardous substances. A Community Engagement Core C (CEC) will address contaminated drinking water problems in California in collaboration with Projects 1, 5 and 6 and Core E, a Data Science and Laboratory Core that will assist researchers and the CEC in meeting their goals. A Research Translation Core C will facilitate interactions between investigators and key stakeholders and a Training Core D will develop the next generation of multidisciplinary professionals. The overall goal is to enhance understanding of the relationship between exposure and disease; provide usable tools to improve human health risk assessments; a...