Abstract1. Seventy‐two per cent of the Flathead River catchment (22 241 km2) is federally designated and protected as wilderness or national park. Thus, the catchment remains one of the more pristine areas of its size in the temperate latitudes of the world.2. Discharge in the downstream reaches of the river system outside the protected areas is regulated by three dams for flood control and hydropower production. These dams have blocked natural migration of native fish from Flathead Lake (496 km2) and isolated populations in sub‐catchments. Temperature and erratic flow fluctuations have altered phenologies of river zoobenthos and fish, and in dam tailwaters aquatic biodiversity is drastically reduced in comparison to unregulated segments.3. Ecological problems caused by changing water quality conditions, altered land‐use patterns and introductions of non‐native biota are interactive with the impacts of stream and lake level regulation, thereby emphasizing the complexity of this river–lake ecosystem.4. Mitigation of the effects of regulation is compromised by differing management priorities and regulatory mandates of County, State, Tribal, and Federal agencies responsible for natural resource management within the catchment. Moreover, economic and ecological interests outside the Flathead influence the way flows are regulated within the catchment.5. The most pervasive influences of stream and lake regulation can be ameliorated by retrofitting the hypolimnial release dam with a selective depth outlet structure to allow temperature control, and by controlling changes in flow rates to create a more natural hydrograph in the tailwaters of the large dams. Allowing fish passage by construction of fish ladders is problematic because upstream passage will commingle native species that were isolated upstream by construction of the dams with non‐native species that were introduced subsequently below the dams. Cascading food web interactions elicited by invasions of non‐native biota may offset any advantage to native stocks gained by passage and/or augmentation with hatchery stocks.6. Mitigation must be adaptive in the sense that unanticipated effects and interactions with other management objectives can be documented and alternative action can be implemented.7. This case history of the effects of stream and lake level regulation, and the approaches to management reviewed in this paper, should serve as a lesson in river conservation.