The articles in this volume of Hydrobiologia commemorate the 40th anniversary of the Mississippi River Research Consortium by synthesizing research and monitoring conducted on the river over the past 40 years. This article briefly describes the recent history of development (since 1866) of the river and the programs that currently support monitoring, research, and rehabilitation of the river. These programs have generated much of the information reported in the articles, which cover hydrology and geomorphology, contaminants, nutrients, plants, reptiles and amphibians, food webs, and concepts of river ecology. The Upper Mississippi River is still responding to changes that occurred 70 or more years ago (construction of navigation dams, leveeing of the floodplains, and intensification of agriculture in the catchment) and to new stressors (climate change, invasive species, hormone-disrupting chemicals). Nevertheless, the river continues to attract 12 million visitors per year along the scenic Great River Road, hosts 36% of all the migrating ducks in the contiguous United States, and is home to 129 native species of freshwater fishes. The biological productivity and diversity of the river are likely to be maintained and even enhanced if the following occur: (1) planned rehabilitation efforts are coupled with hypothesis testing (adaptive environmental assessment and management); (2) sampling is extended beyond the six river reaches that are currently monitored intensively; (3) new sensor networks are developed and deployed; (4) water quality is protected by better controls on nonpoint sources and better testing of new chemicals before they are widely introduced; and (5) ways are found to engage multidisciplinary teams of academic scientists around the world, as well as agency scientists and managers, in cooperative efforts to better understand and manage large, complex, dynamic floodplain–river ecosystems.