The Upper Mississippi River System (UMRS) is a geographically diverse basin extending 10° north temperate latitude that has produced fishes for humans for millennia. During European colonization through the present, the UMRS has been modified to meet multiple demands such as navigation and flood control. Invasive species, notably the common carp, have dominated fisheries in both positive and negative ways. Through time, environmental decline plus reduced economic incentives have degraded opportunities for fishery production. A renewed focus on fisheries in the UMRS may be dawning. Commercial harvest and corresponding economic value of native and non-native species along the river corridor fluctuates but appears to be increasing. Recreational use will depend on access and societal perceptions of the river. Interactions (e.g., disease and invasive species transmission) among fish assemblages within the UMRS, the Great Lakes, and other lakes and rivers are rising. Data collection for fisheries has varied in intensity and contiguousness through time, although resources for research and management may be growing. As fisheries production likely relies on the interconnectivity of fish populations and associated ecosystem processes among river reaches (e.g., between the pooled and unpooled UMRS), species-level processes such as genetics, life-history interactions, and migratory behavior need to be placed in the context of broad ecosystem- and landscape-scale restoration. Formal communication among a diverse group of researchers, managers, and public stakeholders crossing geographic and disciplinary boundaries is necessary through peer-reviewed publications, moderated interactions, and the embrace of emerging information technologies.