The central water management issue for the Nile River basin, as in many other river basins throughout the world, is sustainability of water supply in the context of intense population growth, recurring drought, and increasing competition for water. The issue gets complicated as a result of global climate change that is taking place at an alarming rate. A serious discussion of these and other important water resource issues and the challenges in the basin is necessary and needs our attention to seek solutions and insure sustainability of the water supply. This chapter addresses the physical and hydrological conditions of the basin as a background and present the cross-cutting issues of concern in the basin. The uncertainty of availability of water in the face of climate variability and increased land degradation will be also discussed. The challenges to obtain, protect, and manage the basin’s water supply and ecosystem will also be discussed. Even though one cannot make a meticulous coverage of all the issues and challenges in the basin, a serious attempt was made to present possible solutions at local and regional scale. The solution will be geared towards getting more of the water, using it as much, and making it sustainable.