Exposures at the workplace contribute to many non-communicable diseases (NCDs) with a similar magnitude as urban air pollution or obesity. Given the associated societal and economic (2-6% GDP) pressure, ensuring a healthy work environment is a strategic goal for the European Commission. Demographic changes (aging workforce, female workers) and the rapidly changing nature of work with respect to secure employment and migration, are posing additional challenges. We define the working-life exposome as all occupational and related non-occupational factors (general and socio-economic environment, lifestyle, behaviour). Taking a working-life exposome approach will help address these challenges by providing better insights in how complex working-life exposures are related to NCDs, for vulnerable groups (female, migrant, insecure job workers) or life stages. The working-life exposome is in its infancy and new approaches and methods are needed. In EPHOR a consortium of exposure, health and data scientists and technology developers will develop a working-life exposome toolbox, with stakeholder involvement. The toolbox will make available to scientists, policy makers and occupational health practitioners: 1) innovative methods for collection, storage, and interpretation of more complete and individual level working life exposome data; 2) better knowledge on how the working life exposome relates to NCDs, including complex interactions, vulnerability, biological pathways and early signs of health damage, by uniquely combining large-scale pooling of existing cohorts with focused case studies; 3) models for assessing the economic and societal impact of working life exposures. EPHOR will lay the groundwork for evidence-based and cost-effective preventive actions to reduce the burden of NCDs as a result of the working-life exposome. Thereby, health, wellbeing and productivity of the EU population will be improved and the burden on the EU health care systems reduced. EPHOR is part of the European Human Exposome Network comprised of 9 projects selected from this same call.