Two decades after the construction of the first major dam, the Mekong basin and its six riparian countries have seen rapid economic growth and development of the river system. Hydropower dams, aggregate mines, flood-control dykes, and groundwater-irrigated agriculture have all provided short-term economic benefits throughout the basin. However, it is becoming evident that anthropic changes are significantly affecting the natural functioning of the river and its floodplains. We now ask if these changes are risking major adverse impacts for the 70 million people living in the Mekong Basin. Many livelihoods in the basin depend on ecosystem services that will be strongly impacted by alterations of the sediment transport processes that drive river and delta morpho-dynamics, which underpin a sustainable future for the Mekong basin and Delta. Drawing upon ongoing and recently published research, we provide an overview of key drivers of change (hydropower development, sand mining, dyking and water infrastructures, climate change, and accelerated subsidence from pumping) for the Mekong's sediment budget, and their likely individual and cumulative impacts on the river system. Our results quantify the degree to which the Mekong delta, which receives the impacts from the entire connected river basin, is increasingly vulnerable in the face of declining sediment loads, rising seas and subsiding land. Without concerted action, it is likely that nearly half of the Delta's land surface will be below sea level by 2100, with the remaining areas impacted by salinization and frequent flooding. The threat to the Delta can be understood only in the context of processes in the entire river basin. The Mekong River case can serve to raise awareness of how the connected functions of river systems in general depend on undisturbed sediment transport, thereby informing planning for other large river basins currently embarking on rapid economic development.