We assess possible modifications in the hydrological behaviour of the Rhone River and its tributaries at Lyon (France). We identify changes during the late-twentieth century based on observations and characterise potential impacts of climatic changes on river response by the end of the century. Different scenarios of the latest generation of IPCC AR5 CMIP5 and hydrological modelling were used and included two scenarios for future outlet discharge of Lake Geneva (Switzerland). We show that discharges in the Rhone basin are likely to decrease significantly by the end of the century and that the seasonality of run-off will change substantially as well. In addition, projections point to smaller discharge during low flows, but higher low flows in its sub-basins. Regarding floods, high flows exhibit a general tendency to decrease, whereas potential upwards can be observed for the more extreme floods (less frequent). The approach reported in this paper will help to reflect on the governance modalities of a transboundary river such as the Rhone, especially when water management depends on concession contracts, which are usually granted for several decades and typically last between 60 and 90 years.