Climate change and rapidly rising global water demand are expected to place unprecedented pressures on already strained water resource systems. Successfully planning for these future changes requires a sound scientific understanding of the timing, location, and magnitude of climate change impacts on water needs and availability-not only average trends but also interannual variability and quantified uncertainties. In recent years, two types of large-ensemble runs of climate projections have become available: those from groups of more than 20 different climate models and those from repeated runs of several individual models. These provide the basis for novel probabilistic evaluation of both projected climate change and the resulting effects on water resources. Using a broad range of available ensembles, this research explores the spatial and temporal patterns of high confidence as well as uncertainty in projected river runoff, irrigation water requirements, basin storage yield, and cost estimates of adapting regional water systems to maintain historical supply. Projections of river runoff show robust between-ensemble agreement in regional drying (e.g., southern Africa and southern Europe) and wetting trends (e.g., northeastern United States). By integrating runoff over space and time, the economic effects of adapting supply systems to 2050 water availability show still broader trend agreement across ensembles. That agreement, obtained across such a wide range of multiple-member climate model ensembles in some locations, suggests a high degree of confidence in direction of change in water availability and provides clearer signals for longer-term investment decisions in water infrastructure.