Stress is the ‘buzzword’ of modern life and impacts all aspects of daily life. When stress occurs frequently, remains high for sustained periods of time, and/or overwhelms people’s resources, it can cause mental and cardiometabolic disease. The NWO gravitation project Stress-in-Action capitalizes on the fast advances in technology and big data analytics to move stress research from the lab to daily life. A theoretical framework of daily-life stress will be developed using the novel insights from ambulatory assessments in large, long-running Dutch cohorts and from experimental validation studies. This generates novel, mechanistic understanding of 1) how responses to daily-life stress arise from the temporal, dynamic interplay between context and person-specific factors, 2) how daily-life stress can be reliably measured in a specific individual in real-time, and 3) how and when potential beneficial stress-response mechanisms turn into detrimental effects on mental and cardiometabolic health. This will enable the development of novel monitoring and intervention strategies to track and reduce daily-life stress and its health impact.