Regional information on climate change is urgently needed but often deemed unreliable. To achieve credible regional climate projections, it is essential to understand underlying physical processes, reduce model biases and evaluate their impact on projections, and adequately account for internal variability. In the tropics, where atmospheric internal variability is small compared to the forced change, advancing our understanding of the long-term coupling between changes in upper ocean temperature and the atmospheric circulation will help most to narrow uncertainty. In the extratropics, relatively large internal variability introduces substantial uncertainty, while exacerbating risks associated with extreme events. Large ensemble simulations are essential to estimate the probabilistic distribution of climate change on regional scales. We conclude that the current priority is to understand and reduce uncertainties on scales > 100 km to facilitate assessments at finer scales.(5557 words in text, 134 words for preface)