This study assesses water stress by 2050 in river basins facing increasing human and climatic pressures, by comparing the impacts of various combinations of possible future socio-economic and climate trends. A modelling framework integrating human and hydro-climatic dynamics and accounting for interactions between resource and demand at a 10-day time step was developed and applied in two basins of different sizes and with contrasted water uses: the Herault (2500 km2, France) and the Ebro (85 000 km2, Spain) basins. Natural streamflow was evaluated using a conceptual hydrological model (GR4j). A demand-driven reservoir management model was designed to account for streamflow regulations from the main dams. Urban water demand was estimated from time series of population and monthly unit water consumption data. Agricultural water demand was computed from time series of irrigated area, crop and soil data, and climate forcing. Indicators comparing water supply to demand at strategic resource and demand nodes were computed. This framework was successfully calibrated and validated under non-stationary human and hydro-climatic conditions over the last 40 years before being applied under four combinations of climatic and water use scenarios to differentiate the impacts of climate- and human-induced changes on streamflow and water balance. Climate simulations from the CMIP5 exercise were used to generate 18 climate scenarios at the 2050 horizon. A baseline water use scenario for 2050 was designed based on demographic and local socio-economic trends. Results showed that projected water uses are not sustainable under climate change scenarios.