The Wadden Sea is one of the largest intertidal areas in the world and has been designated as a UNESCO World Heritage Site in recognition of its unique natural features. Major changes in the morphology and ecology of the Wadden Sea over the past millennium resulted from increasing anthropogenic influences such as coastal protection, land claim from the sea and drainage of wetland for agriculture, exploitation of natural resources from hunting and fishing to the extraction of groundwater, gas and oil, industrialisation at port locations and tourism at the islands. A sustainable future can only be achieved if policy and management are backed by solid science. Many of the anticipated changes result from the upscaling of pressures on the Wadden Sea system. Economic globalization leads to upscaling of fisheries, tourism and industrial activities, and thus to changed pressures on space and nature. Climate change will lead to changes in hydrographic patterns, species distribution and possibly tourism; through sea-level rise it will put pressure on coastal protection and the extent of intertidal areas. Invasions of exotic species will transform the ecosystem. There are three major related challenges to management: 1. Nature conservation in a changing system requires a focus on preservation of the values and not the state of the system; 2. The adaptation of the management structure to the scale increase of the pressures, so that local and regional management becomes better nested in transregional and transnational governance structures; 3. Finally, the management approach needs to deal with increasing uncertainty in external forcing of the system, as well as with nonlinearities in system dynamics when it is pushed outside its normal range of operation. Based on these pressures and management challenges, we advocate an integrated social-ecological systems approach for the scientific study and the science-based management of the Wadden Sea Region. The essential characteristics of this approach are strong interdisciplinarity and a focus on aspects of scale and cumulative processes.