Impact of climate change on streamflow in the Upper Mississippi River Basin is evaluated by use of a regional climate model (RCM) coupled with a hydrologic model, Soil and Water Assessment Tool (SWAT). 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 streamflow data using observed weather data and inputs from the U.S. Environmental Protection Agency Better Assessment Science Integrating Point and Nonpoint Sources (BASINS) geographic information systems/database system. Combined performance of SWAT and RCM was examined using observed weather data as lateral boundary conditions in the RCM. The SWAT and RCM performed well, especially on an annual basis. Potential impacts of climate change on water yield and other hydrologic budget components were then quantified by driving SWAT with current and future scenario climates. Twenty-one percent increase in future 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 Upper Mississippi River Basin on an annual basis. Uncertainty analysis showed that the simulated change in streamflow 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 plus regional) and impact assessment modeling (SWAT) “noise.”