The access of almost all 270 million U.S. residents to reliable, safe drinking water distinguishes the United States in the twentieth century from that of the nineteenth century. The United States is a relatively water-abundant country with moderate population growth; nonetheless, current trends are sufficient to strain water resources over time, especially on a regional basis. We have examined the areas of public water infrastructure, global climate effects, waterborne disease (including emerging and resurging pathogens), land use, groundwater, surface water, and the U.S. regulatory history and its horizon. These issues are integrally interrelated and cross all levels of public and private jurisdictions. We conclude that U.S. public drinking water supplies will face challenges in these areas in the next century and that solutions to at least some of them will require institutional changes.