Liver disease is a major global health problem. Fatty liver disease, or excess accumulation of lipids in hepatocytes, affects more than 25% of the worldwide adult population, but children and adolescents may also be affected. Chronic liver disease may progress to cirrhosis and liver cancer resulting in liver-related death or transplantation. Liver disease also impacts the development of diabetes and cardiovascular disease. Liver diseases may be caused or influenced by exposures to environmental chemicals, but this is an understudied area. To address these problems, this project establishes a major integrative and collaborative research program, the Environmental Liver Disease Revolutionizing Innovative, Visionary Environmental Health Research Program (ELD-RIVER). ELD-RIVER will have a transformative impact in the field. The project investigates two broad scientific themes: (i) the impact of endocrine and metabolism disrupting chemicals (EDCs/MDCs) in fatty liver disease, and (ii) other liver diseases (such as liver cancer) associated with chemical exposures. The ELD-RIVER takes a broad integrative scientific approach by investigating relevant chemicals; nutrient:chemical interactions; both animal models and human subjects; and both sexes through state-of-the-art methods including multi-‘omics. EDC/MDC exposures may also impact liver disease through their effects on obesity and diabetes. Thus, obesity and diabetes endpoints will also be evaluated. While the specific projects are expected to evolve over time, the initial work focusses on exposures to polychlorinated biphenyls and vinyl chloride. Both of these chemicals currently rank in the top five in the Agency for Toxic Substances and Disease Registry (ATSDR) Substance Priority List. ELD-RIVER strictly adheres to the principles of scientific rigor and reproducibility and data transparency and availability. ELD-RIVER leverages existing collaborations between multiple organizations including academia, government agencies, industry, and scientific/medical societies. The vision is for ELD-RIVER to become the global hub for environmental liver disease research. To accomplish its translational mission, the program integrates the work of basic scientists, epidemiologists, and physicians. The project will also develop diagnostic biomarkers, new treatments, practice guidelines, and it has the potential to impact policy change. Along the way, unique institutional education/training resources will be utilized so that ELD-RIVER will help produce the next generation of environmental health scientists. The work proposed is relevant to Strategic Plan of the National Institute of Environmental Health Sciences (Themes 1, 2, and 5 and Goals 1, 4, 7, and 8).