Faced by the realities of a changing climate, decision makers in a wide variety of organizations are increasingly seeking quantitative predictions of regional and local climate. An important issue for these decision makers, and for organizations that fund climate research, is what is the potential for climate science to deliver improvements—especially reductions in uncertainty—in such predictions? Uncertainty in climate predictions arises from three distinct sources: internal variability, model uncertainty, and scenario uncertainty. Using data from a suite of climate models, we separate and quantify these sources. For predictions of changes in surface air temperature on decadal timescales and regional spatial scales, we show that uncertainty for the next few decades is dominated by sources (model uncertainty and internal variability) that are potentially reducible through progress in climate science. Furthermore, we find that model uncertainty is of greater importance than internal variability. Our findings have implications for managing adaptation to a changing climate. Because the costs of adaptation are very large, and greater uncertainty about future climate is likely to be associated with more expensive adaptation, reducing uncertainty in climate predictions is potentially of enormous economic value. We highlight the need for much more work to compare (a) the cost of various degrees of adaptation, given current levels of uncertainty and (b) the cost of new investments in climate science to reduce current levels of uncertainty. Our study also highlights the importance of targeting climate science investments on the most promising opportunities to reduce prediction uncertainty.