As adaptation becomes more tightly integrated into the range of responses to climate change, understanding how knowledge of climate change impacts and vulnerabilities can be effectively used is essential both to direct research and to support action. This article reviews literature along an intellectual transect from knowledge of climate impacts on water systems to the influence of that knowledge on adaptation responses. We discuss scientific evidence for changing hydroclimatic regimes, methods for translating climatic information into results relevant to adaptation, uncertainties in these results, methods for addressing uncertainty via adaptation processes, challenges and opportunities for knowledge development and transfer, and sociopolitical factors that enable or hinder the use of knowledge. Challenges remain in developing and applying methods for identifying and reducing underlying vulnerabilities and reliably connecting technical knowledge of climate impacts with local needs remains an unsolved problem. But new decision-making methods and the potential to learn from analogous water management situations provide hope for near-term progress.