We develop a water resource system model of the US (WRS-US) that identifies 99 river basins. The model is built on river basin-specific estimates of water requirements for thermoelectric cooling, irrigation, public supply, self-supply and mining. WRS-US allocates water resources across uses in order to minimize water stress over the year in each river basin. We use the model to predict water stress through to 2050 under two climate policies and two climate models. The largest water stresses are predicted to occur in the South West of the US. Average water stress is not expected to be alleviated by a constrained GHG emission policy by 2050. However, the mitigation policy will reduce inter-annual variability of water stress.