Sustainable river basin management is a wide concern currently. However, some quantitative indicators are still needed to make the principle of sustainability more accessible for decision making. One particular question regarding sustainable river basin management is: How much water in a river is needed for sustaining both human activities (including the current ones and projected new developments in the future) and ecosystem integrity? This study assesses water availability with consideration of climatic and hydrologic conditions, water supply infrastructure and water management institutions in the context of river basins. A management model at the river basin scale is applied to assess not only human water demand and supply for domestic, industrial, and agricultural sectors, but also natural demands. Four different indicators: "Criticality Ratio" (CR), "Depletion Ratio" (DR), "Human Impact Ratio" (HR) and "Outflow Ratio" (OR) are used to assess the impact of human interferences on the environment of a river basin. The model and indicators are applied to the major river basins in the U.S., and the result shows that CR is close or greater than 1.0 (withdrawal is more than the renewable water) in the basins of western U.S.; the average value of these indicators will not change significantly during the next 20 years in most of the basins in the U.S.; the variation of CR will become larger in some basins such as California (water region) and Columbia. For the basins with large average CR or large variation, water saving actions should be undertaken; for other basins, there still remains some capacity for additional human uses, but the new development should be assessed very carefully.