Determining the genetic diversity of unionid populations is important for the preservation of the species and ecosystems in which they reside. The Yellow lampmussel, Lampsilis cariosa, is an endangered unionid found along the Atlantic Slope drainages in the United States and Canada. Along with many other North American unionid species, L. cariosa populations are declining. In order to enhance conservation efforts, the genetic structure and diversity of current populations must be examined. A sample of 178 individuals of L. cariosa from 20 populations in the Susquehanna and Delaware River drainages, and two different river populations in Maine were genotyped at the mitochondrial cytochrome oxidase subunit one (COI) gene and seven microsatellite loci. Haplotype genetic diversity for L. cariosa was low, while nucleotide diversity was high. Analysis of mtDNA showed significant population structure but lower than that of other mussel species. Our results indicate past gene flow among populations found in the Susquehanna and Delaware drainages with recent demographic expansion. As an endangered species with currently small population sizes, conservation efforts for L. cariosa should focus on protecting genetic diversity by preserving the largest populations in different drainages.