We aim to understand and assess the complex interactions and cumulative effects of multiple stressors on river systems over time scales of several decades. Hydrological processes and extremes greatly impact the dynamics of other stressors, but the interactions remain poorly understood, particularly at larger scales. Our research will investigate long-term multi-stressor trajectories in Central Europe, based on large-scale model simulations. We will (1) couple a large-scale hydrological model with a groundwater model to simulate the dynamics of flows between surface water and groundwater, for the first time representing low flow conditions and desiccation events in Central European catchments over 70 years; (2) simulate water temperature, biological oxygen demand, salinity and their interactions in relation to hydrology; (3) analyse the spatio-temporal patterns of long-term degradation and recovery trajectories focusing on low flows and desiccation events that trigger stressor cascades; (4) assess the impact of climate change and human activities on river discharge; and (5) cooperate with other RESIST projects to upscale biotic consequences of hydrological changes to the Central European scale. This project tests Main Hypothesis MH 1.1 of RESIST, focusing on the assessment of low flow and desiccation events in river ecosystems that trigger multiple stressor effects at the catchment scale. In contrast to RESIST’s other hydrological project (A14), we will simulate stressor interactions at the large scale in Central European catchments, yet will collaborate with A14 on process understanding gained in the case study Kinzig and on complementary data analyses. In Phase II, A24 will assess, understand, and simulate the baseline conditions, long-term trajectories, and stressor interactions in Central European catchments at a spatio-temporal resolution that is relevant to the biota and required by the partner projects. This will be achieved through data collection, data analysis and improvement of simulations of the ReWaterGAP/WaterGAP3 modelling framework. We will analyse the dynamics of multiple stressors, i.e. stressor cascades caused by short and prolonged drought events, under changing climate conditions and the value of using counterfactual climate data to explore the contribution of climate change impacts (i.e. climate-related systems). The project is fundamental to upscaling efforts and will provide a deeper understanding of the contribution of climate change to the timing of degradation, which is essential for the assessment of primary and secondary stressors.