In order to understand the development and changes of fundamental water-related challenges, the inherent relationship between river system evolution and those challenges, as well as basic characteristics, development, and variation conditions, were analyzed on the basis of previous studies. It is pointed that river system evolution and drastic changes are the source of the four water-related challenges referred to in this paper as too much water, too little water, muddy water, and dirty water, which result in significant harm to material civilization and ecological civilization construction. With social progress and environmental changes in river systems comes a large amount of development and variation of fundamental water-related challenges. The too much water challenge includes greater flood frequency, large flooding disasters even with small amounts of water in rivers, imbalanced river regulation, and flooding of cities. The too little water challenge includes increasing frequency of drought and water shortage, regional and connotation expansion, lengthening of the duration, and so on. Muddy water challenges include frequent human activities in the basin, and large decreases in river sediment discharge and its influences. Dirty water problems include significant compound pollution and non-point source pollution, and the shift from mainly industrial pollution to mainly biological pollution. Attention must be given to some new conditions and new characteristics of fundamental water-related challenges.