The Meramec River basin in east-central Missouri has one of the most diverse unionoid mussel faunas in the central United States with >40 species identified. Data were analyzed from historical surveys to test whether diversity and abundance of mussels in the Meramec River basin (Big, Bourbeuse, and Meramec rivers, representing >400 river miles) decreased between 1978 and 1997. We found that over 20y, species richness and diversity decreased significantly in the Bourbeuse and Meramec rivers but not in the Big River. Most species were found at fewer sites and in lower numbers in 1997 than in 1978. Federally endangered species and Missouri Species of Conservation Concern with the most severe temporal declines were Alasmidonta viridis, Arcidens confragosus, Elliptio crassidens, Epioblasma triquetra, Fusconaia ebena, Lampsilis abrupta, Lampsilis brittsi, and Simpsonaias ambigua. Averaged across all species, mussels were generally being extirpated from historical sampling sites more rapidly than colonization was occurring. An exception was one reach of the Meramec River between river miles 28.4 and 59.5, where mussel abundance and diversity were greater than in other reaches and where colonization of Margaritiferidae, Lampsilini, and Quadrulini exceeded extirpation. The exact reasons mussel diversity and abundance have remained robust in this 30- mile reach is uncertain, but the reach is associated with increased gradients, few long pools, and vertical rock faces, all of which are preferable for mussels. Complete loss of mussel communities at eight sites (16%) with relatively diverse historical assemblages was attributed to physical habitat changes including bank erosion, unstable substrate, and sedimentation. Mussel conservation efforts, including restoring and protecting riparian habitats, limiting the effects of in-stream sand and gravel mining, monitoring and controlling invasive species, and protecting water quality, may be warranted in the Meramec River basin.