The Colorado River Basin supplies water to roughly 40 million people in the south-western United States. A complex interstate regime that has evolved across the past century governs allocation and management of these coveted flows, and formidable challenges face this regime in contemporary times – a historical era aptly dubbed the ‘era of limits’. This paper illuminates these challenges and offers modest input regarding potential responses to them. We initially survey the evolution of the interstate water regime and outline its essential features as well as those of the basin. We then turn to the contemporary challenges and potential responses, which generally concern an unprecedented imbalance between water supplies and demands, long-standing disagreements over the meaning of the Colorado River Compact, water rights held by American Indian tribes on reservations throughout the basin, and ongoing biodiversity protection and salinity control efforts. We conclude by reflecting on lessons from and for the Colorado River Basin vis-à-vis the interstate water regimes existent in the other four basins encompassed within the Harvard Water Federalism Project.