Human demands on the world’s available freshwater supplies continue to grow as the global population increases. In the endeavor to manage water to meet human needs, the needs of freshwater species and ecosystems have largely been neglected, and the ecological consequences have been tragic. Healthy freshwater ecosystems provide a wealth of goods and services for society, but our appropriation of freshwater flows must be better managed if we hope to sustain these benefits and freshwater biodiversity. We offer a framework for developing an ecologically sustainable water management program, in which human needs for water are met by storing and diverting water in a manner that can sustain or restore the ecological integrity of affected river ecosystems. Our six-step process includes: developing initial numerical estimates of key aspects of river flow necessary to sustain native species and natural ecosystem functions; accounting for human uses of water, both current and future, through development of a computerized hydrologic simulation model that facilitates examination of human-induced alterations to river flow regimes; assessing incompatibilities between human and ecosystem needs with particular attention to their spatial and temporal character; collaboratively searching for solutions to resolve incompatibilities; conducting water management experiments to resolve critical uncertainties that frustrate efforts to integrate human and ecosystem needs; and designing and implementing an adaptive management program to facilitate ecologically sustainable water management for the long term. Drawing from case studies around the world to illustrate our framework, we suggest that ecologically sustainable water management is attainable in the vast majority of the world’s river basins. However, this quest will become far less feasible if we wait until water supplies are further over-appropriated.