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This study assesses potential changes in runoff of California's eight major Central Valley water supply watersheds in the 21st century. The study employs the latest operative climate projections from 10 general circulation models (GCMs) of the Coupled Model Intercomparison Project Phase 5 (CMIP5) under two emission scenarios (RCP 4.5 and RCP 8.5) to drive a hydrologic model (VIC) in generating runoff projections through 2099. Changes in peak runoff, peak timing, seasonal (major water supply season April-July) runoff, and annual runoff during two future periods, mid-century and late-century, relative to a historical baseline period are examined. Trends in seasonal and annual runoff projections are also investigated. The results indicate that watershed characteristics impact runoff responses to climate change. Specifically, for rain-dominated watersheds, runoff is generally projected to peak earlier with higher peak volumes on average. For snow-dominated watersheds, however, runoff is largely projected to peak within the same month as historical runoff has, with little changes in peak volume during mid-century but pronounced decreases during late-century under the higher emission scenario. The study also identifies changes that are common to all study watersheds. Specifically, the temporal distribution of annual runoff is projected to change in terms of shifting more volume to the wet season, though there is no significant changing trend in the total annual runoff. Additionally, the snowmelt portion of the total annual runoff (represented by April-July runoff divided by total annual runoff) is projected to decline consistently under both emission scenarios, indicative of a shrinking snowpack across the study watersheds. Collectively, these changes imply higher flood risk and lower water supply reliability in the future that are expected to pose stress to California's water system. Those findings can inform water management adaptation practices (e.g., watershed restoration, re-operation of the current water system, investing in additional water storage) to cope with the stress.