Freshwater bivalves of the order Unioniformes represent the largest bivalve radiation in freshwater. The unioniform radiation is unique in the class Bivalvia because it has an obligate parasitic larval stage on the gills or fins of fish; it is divided into 6 families, 181 genera, and ∼800 species. These families are distributed across 6 of the 7 continents and represent the most endangered group of freshwater animals alive today. North American unioniform bivalves have been the subject of study and illustration since Martin Lister, 1686, and over the past 320 y, significant gains have been made in our understanding of the evolutionary history and systematics of these animals. Here, the current state of unioniform systematics and evolution is summarized, and suggestions for future research themes are proposed. Advancement in the areas of systematics and evolutionary relationships within the Unioniformes will require a resurgence of survey work and reevaluation of all taxa, especially outside of North America and Western Europe. This work will require collection of animals for shell morphology, comparative anatomy, and molecular analyses. Along with reexamination of described taxa, a renewed emphasis on the natural history, host-fish relationships, ecology, and physiology of these animals is needed. Traditional conchological and anatomical characters should be reevaluated, new character suites should be added, and new morphometric methods should be applied. The fossil record of freshwater bivalves should be carefully reviewed, and phylogenetic hypotheses including fossil taxa must be developed. We will have to expand our set of molecular tools to include or develop additional markers, such as single-copy nuclear genes and microsatellites. Examination of double uniparental inheritance of mitochondrial deoxyribonucleic acid (DNA) is providing new insights into the evolution of this order. Mitochondrial gene order differs among genera but is still to be explored. Expansion of our understanding of the evolutionary relationships and history of unioniform bivalves will provide a solid foundation to study the zoogeography of these rather sessile, obligate freshwater organisms. The unique natural history of unioniform bivalves provides a fertile area for testing and developing evolutionary theories, and, as our understanding of the systematics of these animals improves, a better understanding of the evolution of this expansive radiation in freshwater will develop.