The Main river is a major European waterway, located in the heart of Europe. It is the largest eastern tributary to the Rhine river and connects the North Sea to the Black Sea via the Main-Danube canal, bridging the European water divide. The Main river basin is a densely populated and intensively used area of about 25,000 km² which is already subject to significant challenges and competitions for its water, land and energy. The effects of climate change are expected to lead to a strong increase of summer droughts and heatwaves due to significantly higher temperatures and a strong decrease of summer precipitation. At the same time, the risk of winter floods increases significantly due to heavier precipitation in this season. This will have considerable consequences for almost all actors in agriculture, forestry, water and energy management. A fundamental and forward-looking revision of available resource management measures is essential for ensuring a climate change resilient development of the region.