We examine the spatial variability of the response of aquifer systems to climate change in and adjacent to the Cascade Range volcanic arc in the Deschutes Basin, Oregon using downscaled global climate model projections to drive surface hydrologic process and groundwater flow models. Projected warming over the 21st century is anticipated to shift the phase of precipitation toward more rain and less snow in mountainous areas in the Pacific Northwest, resulting in smaller winter snowpack and in a shift in the timing of runoff to earlier in the year. This will be accompanied by spatially variable changes in the timing of groundwater recharge. Analysis of historic climate and hydrologic data and modeling studies show that groundwater plays a key role in determining the response of stream systems to climate change. The spatial variability in the response of groundwater systems to climate change, particularly with regard to flow-system scale, however, has generally not been addressed in the literature. Here we simulate the hydrologic response to projected future climate to show that the response of groundwater systems can vary depending on the location and spatial scale of the flow systems and their aquifer characteristics. Mean annual recharge averaged over the basin does not change significantly between the 1980s and 2080s climate periods given the ensemble of global climate models and emission scenarios evaluated. There are, however, changes in the seasonality of groundwater recharge within the basin. Simulation results show that short-flow-path groundwater systems, such as those providing baseflow to many headwater streams, will likely have substantial changes in the timing of discharge in response changes in seasonality of recharge. Regional-scale aquifer systems with flow paths on the order of many tens of kilometers, in contrast, are much less affected by changes in seasonality of recharge. Flow systems at all spatial scales, however, are likely to reflect interannual changes in total recharge. These results provide insights into the possible impacts of climate change to other regional aquifer systems, and the streams they support, where discharge points represent a range of flow system scales.