Abstract: The source region of major rivers in Southwestern China (MRSC), featured by prevalence of glacier, snow, and frost, serve as the strategic reserves of water resources for the people in the region and downstream. Its hydrological and biogeochemical processes have been subject to rapid change driven by warming climate. However, its driving mechanism and future trend remain unclear especially when compounded by human activities. To gain a better understanding of the hydrological and biogeochemical change in this region to facilitate sustainable management, the National Natural Science Foundation of China launched the major research plan "runoff change and its adaptive management in the source region of major rivers in Southwestern China" in 2015. Since the implementation of the Major Research Plan, substantial progresses have been achieved : an integrated monitoring system was established based on innovative ground based and remote sensing technologies, which significantly improved the monitoring capability in this region; the runoff generation mechanisms and the co-evolution of water-vegetation-soil system on the plateau were investigated; an isotope-aided hydrological model coupling snow, glacier and frost processes was established; the historical change and future pattern of runoff of the major rivers were explored; an all-material-flux theory for river ecosystem study was proposed, and an integrated monitoring and detecting approach was established for all-material-flux study. The biogeochemical cycle of the source region and the cumulative effect of the cascade reservoirs on this cycle were quantified; a water-food-energy-ecosystem nexus approach was developed with the aim to better operate hydropower plants in a sustainable and cooperative manner. This article reviews the above main progress and achievements of the major research plan.