The recorded runoff of the Yellow River presented significant decline trend due to environmental change, which has been highly threatening water security and in order to meet the major needs of the national strategy of ecological protection and high-quality development of the Yellow River Basin, this paper formulates key scientific issues and key techniques that urgently need to be solved in runoff effects under changing environments. Taking the water source conservation area of the Yellow River Basin as a case study area, with focusing on runoff response to environmental changes and water resources prediction, four future research contents of data set construction, mechanism analysis, model development, and trend prediction are proposed. The expected research achievements will reveal the coupling mechanisms of hydrological-ecological processes in water conservation area, innovate eco-hydrological simulation and prediction technology, predict the trend of water security and eco-environmental risk under changing environment, and provide strong supports to the decision of sustainable water resources utilization and eco-environmental protection in the Yellow River Basin, which will produce remarkable scientific value, huge socioeconomic and ecological benefits. Keywords: environmental change; eco-hydrological processes; water resources; ecological security; Yellow River water source conservation area