Water is at the center of a complex and dynamic system involving climatic, biological, hydrological, physical, and human interactions. We demonstrate a new modeling system that integrates climatic and hydrological determinants of water supply with economic and biological drivers of sectoral and regional water requirement while taking into account constraints of engineered water storage and transport systems. This modeling system is an extension of the Massachusetts Institute of Technology (MIT) Integrated Global System Model framework and is unique in its consistent treatment of factors affecting water resources and water requirements. Irrigation demand, for example, is driven by the same climatic conditions that drive evapotranspiration in natural systems and runoff, and future scenarios of water demand for power plant cooling are consistent with energy scenarios driving climate change. To illustrate the modeling system we select “wet” and “dry” patterns of precipitation for the United States from general circulation models used in the Climate Model Intercomparison Project (CMIP3). Results suggest that population and economic growth alone would increase water stress in the United States through mid-century. Climate change generally increases water stress with the largest increases in the Southwest. By identifying areas of potential stress in the absence of specific adaptation responses, the modeling system can help direct attention to water planning that might then limit use or add storage in potentially stressed regions, while illustrating how avoiding climate change through mitigation could change likely outcomes.