Populations of the freshwater mussel genus Anodonta appear to be in a state of rapid decline in western North America, following a trend that unfortunately seems to be prevalent among these animals (Mollusca: Unionoida). Here we describe the patterns of molecular divergence and diversity among Anodonta populations in the Bonneville Basin, a large sub-basin of the Great Basin in western North America. Using amplified fragment length polymorphism (AFLP) analysis, we found a striking lack of nuclear diversity within some of these populations, along with a high degree of structuring among populations (FST = 0.61), suggesting post-Pleistocene isolation, due either to a long-term loss of hydrologic connectivity among populations or to more recent fish introductions. We also found evidence of recent hybridization in one of these populations, possibly mediated by fish-stocking practices. Using mitochondrial sequence data, we compared the Bonneville Basin populations to Anodonta in several other drainages in western North America. We found a general lack of resolution in these phylogenetic reconstructions, although there was a tendency for the Bonneville Basin Anodonta (tentatively A. californiensis) to cluster with A. oregonensis from the adjacent Lahontan Basin in Nevada. We recommend further investigation of anthropogenic factors that may be contributing to the decline of western Anodonta and a broad-scale analysis and synthesis of genetic and morphological variation among Anodonta in western North America.