The US Geological Survey (USGS) is currently (2020) integrating its water science programs to better address the nation’s greatest water resource challenges now and into the future. This integration will rely, in part, on data from 10 or more intensively monitored river basins from across the USA. A team of USGS scientists was convened to develop a systematic, quantitative approach to prioritize candidate basins for this monitoring investment to ensure that, as a group, the 10 basins will support the assessment and forecasting objectives of the major USGS water science programs. Candidate basins were the level-4 hydrologic units (HUC04) with some of the smaller HUC04s being combined; median candidate-basin area is 46,600 km². Candidate basins for the contiguous United States (CONUS) were grouped into 18 hydrologic regions. Ten geospatial variables representing land use, climate change, water use, water-balance components, streamflow alteration, fire risk, and ecosystem sensitivity were selected to rank candidate basins within each of the 18 hydrologic regions. The two highest ranking candidate basins in each of the 18 regions were identified as finalists for selection as “Integrated Water Science Basins”; final selection will consider input from a variety of stakeholders. The regional framework, with only one basin selected per region, ensures that as a group, the basins represent the range in major drivers of the hydrologic cycle. Ranking within each region, primarily based on anthropogenic stressors of water resources, ensures that settings representing important water-resource challenges for the nation will be studied.