We synthesized information on selected contaminants in the Upper Mississippi River, summarized regulatory measures enacted to reduce pollution, and described biotic and ecosystem responses to regulatory actions. Contamination of the river with mercury and lead rapidly followed settlement of the basin by European immigrants in the mid-1800s. Metal contamination peaked in the 1960s and has since decreased substantially. DDT, its degradation product DDE, and PCBs biomagnified to concentrations that adversely affected wildlife in upper trophic levels. National (U.S.A.) environmental regulations enacted from 1972 to 1991 reduced discharges of wastes from point sources, improved wastewater treatment, and reduced or banned the production or usage of certain chemicals, such as DDT, PCBs, and lead. Responses to these regulatory measures include reductions in ecosystem contamination, reductions in biotic exposure, and recovery of affected wildlife populations. Recovery from pollution has been slow, however, and we conclude that proactive approaches focusing on prevention are highly preferable to reactive approaches in management of toxic substances. Past successes in reducing point-source pollution, which is greatest near urban areas, do not extend to nonpoint-source pollution, given that the existing regulatory framework does not adequately address nonpoint sources. The river continues to receive hundreds of recently synthesized chemicals, and the behavior and effects of most of these compounds in aquatic ecosystems are largely unknown. Emerging contaminants and recently discovered mechanisms of adverse biological effects, such as endocrine disruption, pose continuing challenges to scientists and environmental managers concerned with the ecological health of this riverine ecosystem.