Impact of climate change on stream flow in the Upper Mississippi River Basin (UMRB) is evaluated by use of a regional climate model (RCM) coupled with a hydrologic model - Soil and Water Assessment Tool (SWAT). By supplying data for each of the 119 sub-basins of the UMRB, the RCM we used resolves, at least partially, some fine-scale dynamical processes that are important contributors to precipitation in this region and that are not well simulated by global models. The SWAT model was calibrated and validated against measured stream flow data using observed weather data and inputs from the EPA BASINS GIS/database system. Combined performance of the SWAT and RCM was examined using observed weather data as lateral boundary condition in the RCM. The SWAT and RCM were found to perform well, especially on an annual basis, although monthly stream flow estimates contained substantial error. The potential impacts of climate change on water yield and other hydrologic budget components were then quantified by driving SWAT with current and future climates. Twenty one percent increase in future annual precipitation simulated by the RCM produced 18% increase in snowfall, 51% increase in surface runoff, and 43% increase in groundwater recharge, resulting in 50% net increase in total water yield in the UMRB on an annual basis. Uncertainty analysis showed the simulated change in stream flow substantially exceeded model biases of the combined modeling system (with largest bias of 18%). While this does not necessarily give us high confidence in the actual climate change that will occur, it does demonstrate that the climate change “signal” stands out from the climate modeling (global + regional) and impact assessment modeling (SWAT) “noise.”