Climate change is likely to have an impact on the discharge of the European river Rhine. To base adaptation strategies, to deal with these changing river discharges, on the best scientific and technical knowledge, it is important to understand potential climate impacts, as well as the capacity of social and natural systems to adapt. Both are characterized by large uncertainties, at different scales, that range from individual to local to regional to international. This review paper addresses three challenges. Dealing with climate change uncertainties for the development of adaptation strategies is the first challenge. We find that communication of uncertainties in support of river basin adaptation planning generally only covers a small part of the spectrum of prevailing uncertainties, e.g. by using only one model or scenario and one approach to deal with the uncertainties. The second challenge identified in this paper is to overcome the current mismatch of supply of scientific knowledge by scientists and the demand by policy makers. Early experiences with ‘assess-risk-of-policy’ approaches analysis of options, starting from the resilience of development plans, suggests that this approach better responds to policy makers’ needs. The third challenge is to adequately capture the transnational character of the Rhine river basin in research and policy. Development and implementation of adaptation options derived from integrated analysis at the full river basin level, rather than within the boundaries of the riparian countries, can offer new opportunities, but will also meet many practical challenges.