Phylogenetic relationships among vesicomyid clams (Bivalvia: Vesicomyidae) and their placement within the order Heterodonta were examined using mitochondrial encoded cytochrome oxidase subunit I (COI) DNA sequences. The presently analyzed vesicomyids represent a recent monophyletic radiation that probably occurred within the Cenozoic. Nucleotide phylogenetic analyses resolved discrete clades that were consistent with currently recognized species: Calyptogena magnifica, C. ponderosa, Ectenagena extenta, C. phaseoliformis, Vesicomya cordata, Calyptogena n. sp. (Gulf of Mexico), C. kaikoi, C. nautilei, C. solidissima and C. soyoae (Type-A). However, specimens variously identified as: V. gigas, C. kilmeri, C. pacifica, and V. lepta comprised two “species complexes”, each composed of multiple evolutionary lineages. Most taxa are limited to hydrothermal-vent or cold-seep habitats, but the “vent” versus “seep” clams do not constitute separate monophyletic groups. Current applications of the generic names Calyptogena, Ectenagena, and Vesicomya are not consistent with phylogenetic inferences.