ABSTRACT: Changes in global climate may alter hydrologic conditions and have a variety of effects on human settlements and ecological systems. The effects include changes in water supply and quality for domestic, irrigation, recreational, commercial, and industrial uses; in instream flows that support aquatic ecosystems, recreation uses, hydropower, navigation, and wastewater assimilation; in wetland extent and productivity that support fish, wildlife, and wastewater assimilation; and in the frequency and severity of floods. Watersheds where water resources are stressed under current climate are most likely to be vulnerable to changes in mean climate and extreme events. This study identified key aspects of water supply and use that could be adversely affected by climate change, developed measures and criteria useful for assessing the vulnerability of regional water resources and water dependent resources to climate change, developed a regional database of water sensitive variables consistent with the vulnerability measures, and applied the criteria in a regional study of the vulnerability of U.S. water resources. Key findings highlight the vulnerability of consumptive uses in the western and, in particular, the southwestern United States. However, southern United States watersheds are relatively more vulnerable to changes in water quality, flooding, and other instream uses.