Abstract: The relation between Mekong River and Tonle Sap Lake is a representative of the world ’s famous river-lake relationships. It is affected by upstream flows, downstream tides, regional wind and waves, and flood regulation and storage. The superposition and mutual effect of water regime (encounter, reverse flow, flow supplement, overbank flow, backwater and storage) are huge with highly integrated hydrological processes. This paper expounds the research progress of the river-lake relationship between Mekong River and Tonle Sap Lake and the hydrological regime-driven response mechanism from three aspects: the changing law of the hydrological regime of the river and lake, the coupled hydrological and hydrodynamic model of the river and lake, the water exchange relationship between the river and the lake, and the hydrological regime-driven response mechanism. And this paper analyzes key scientific issues and technical realization paths. The results show that the hydrological-hydrodynamic mechanism of the Mekong River and the Tonle Sap Lake is very complex but unclear, which has become a bottleneck problem restricting the comprehensive management of the river and lake. The key research directions that need to be strengthened in the future mainly include: establishing a hydrology-hydrodynamic coupling model of the large-scale connected water network between Mekong River and the Tonle Sap Lake; finely simulating spatial-temporal-amount evolution characteristics of the superposition and combination effect of river and lake; quantitatively revealing the fluvial phase and lacustrine phase transition characteristics of Tonle Sap Lake; clarifying the macro and micro patterns of the interaction law between Mekong River and Tonle Sap Lake; quantitatively assessing the encountering impact of runoff, tide, wind and wave on river-lake water exchange; clarifying the driving mechanism and coupling covariant response law of river-lake water regime-hydrodynamic conditions-water flux interaction-hydrological rhythm in the lake area; creating a knowledge map of quantitative relationship between the connotation change of river-lake water exchange relationship and the process change of hydrological regime in the whole Tonle Sap Lake. The research results show important scientific theoretical significance and practical application value for enriching the connotation of river-lake relationship, guiding the response to flood and drought disasters in Cambodia, improving the accuracy of hydrological forecast, and ensuring the health of river and lake.