Water quality describes the physicochemical characteristics of the water body. These vary naturally with the weather and with the spatiotemporal variation of the water flow, i.e., the flow regime. Worldwide, biota have adapted to the variation in these variables. River channels and their riparian zones contain a rich selection of adapted species and have been able to offer goods and services for sustaining human civilizations. Many human impacts on natural riverine environments have been destructive and present opportunities for rehabilitation. It is a big challenge to satisfy the needs of both humans and nature, without sacrificing one or the other. New ways of thinking, new policies, and institutional commitment are needed to make improvements, both in the ways water flow is modified in rivers by dam operations and direct extractions, and in the ways runoff from adjacent land is affected by land-use practices. Originally, prescribed flows were relatively static, but precepts have been developed to encompass variation, specifically on how water could be shared over the year to become most useful to ecosystems and humans. A key aspect is how allocations of water interact with physicochemical variation of water. An important applied question is how waste releases and discharge can be managed to reduce ecological and sanitary problems that might arise from inappropriate combinations of flow variation and physicochemical characteristics of water. We review knowledge in this field, provide examples on how the flow regime and the water quality can impact ecosystem processes, and conclude that most problems are associated with low-flow conditions. Given that reduced flows represent an escalating problem in an increasing number of rivers worldwide, managers are facing enormous challenges.