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For centuries, rivers have experienced massive changes of their hydromorphic structures due to human activities. The Danube River, the second largest river in Europe, is a case in point for long-term societal imprint. Resulting human-induced pressures are a key issue for river management, aiming to improve the ecological conditions and guarantee the provision of ecosystem services. As the most international river basin in the world, the management of the Danube is particularly challenging and needs a well-organized cooperation of 19 nations. The recent river basin management plan has identified pollution and hydromorphological alterations as most pressing problems, but it has also acknowledged newly emerging issues. In this article, we present 3 specific examples of highly relevant issues for the future river basin management of the Danube: (a) long-term impacts in the catchment such as changes in flood patterns and potential ecological consequences; (b) complex feedback loops linking the spread of neozoa with intertwined stressor responses due to river engineering for different purposes; and (c) linkages between different assessment approaches based on European legal frameworks to analyse the specific pressures at different spatial scales. These examples highlight the need for a more integrated approach in future Danube River Basin management schemes. Furthermore, large-scale effects such as climate change and interactions of multiple pressures need to be addressed in future management to increase resilience of the river system and to allow a sustainable ecosystem-based management of rivers.