The decline of the freshwater mussel fauna of the Ohio River, U.S.A. is compared to the dates of service of the existing dams, the arrival of the exotic zebra mussel, and the presence of urban centers on the mainstem. Based upon historical records we know that most pools supported 20–50 species of mussels; today many have fewer than ten. The results presented here show a mixed effect of the dams on the mussel fauna, ranging from marked deleterious effects in Hannibal, McAlpine, and Smithland pools to comparatively little effect in pools such as Dashields, Greenup, and Markland. In nearly all cases, the most dramatic declines in mussels were associated with the arrival of zebra mussels in the Ohio River in 1991. Pools with significant urban centers often had a loss of diversity well before the construction of dams or the arrival of zebra mussels; these losses are attributed to water quality problems associated with urban centers. Mussel diversity has thus declined in the Ohio River as the result of a three-fold problem: loss of water quality, existing dams, and zebra mussels.