The National Natural Science Foundation of China has launched a major research program entitled “Integrated Study of Eco-hydrological Processes in the Heihe River Basin” (referred to as “Heihe River Program”). It is grounded on the principles of the earth system science, and intended to explore the theory and methods of improving the water use efficiency in the inland river basins of China affected by severe water shortage and ecological deterioration problems. Since the implementation of the Heihe River Program for the past four years, we have established a basin-wide eco-hydrological observation system integrating remote sensing, monitoring and experimentation; developed a comprehensive database and information system; revealed the important coupling mechanism of eco-hydrological processes including glaciers, forests and oases; gained basic understanding of the system characteristics of eco-hydrological units which serve as the basis for computing the basin water cycle and water balance; and quantified the ecological water demand in the lower reaches of the Heihe River as the important constraints for optimal water resources management in the Heihe River Basin. In the next few years, we will integrate comprehensive watershed models supported by high-resolution spatio-temporal data of air, water, biota and economics towards the goal of playing a world-leading role in river science.