The Sphaeriidae, commonly known as (pea,? (pill,? (nut? and (fingernail clams,? are prominent and ubiquitous members of freshwater ecosystems. Sphaeriid clams exhibit various peculiar biological features, including hermaphroditism, self-fertilization, ovoviviparity and pronounced polyploidy. Although this bivalve family has consistently attracted the attention of biologists, most previous discussions of sphaeriid evolution have generally lacked a rigorous phylogenetic perspective. This dissertation addresses this shortcoming by conducting evolutionary studies on the Sphaeriidae, focusing mainly on the subfamily Sphaeriinae, a major subgroup of the family. Chapter 1 reviews the current understanding of sphaeriid taxonomy, classification, reproductive/developmental characters and polyploidy. To demonstrate whether or not polyploidy is widespread in the Sphaeriinae, and, if so, to determine if polyploidy is related to asexuality, chromosomes of various North American taxa are cytogenetically investigated (Chapter 2 and 3). Well over 100 mitotic chromosomes are observed from all the species investigated and spermatogenetic meiosis is observed in octoploid Sphaerium striatinum. Polyploid North American members of sphaeriid genera are characterized for their expressed allelic repertoire of 6-Phosphogluconate- Dehydrogenase (PGD) in order to test hypotheses addressing the evolutionary origins of sphaeriid genome duplication (Chapter 3). Phylogenetic analyses of these PGD alleles suggest an ancient genome duplication event predating the divergence of some North American genera. Using morphological characters, Chapter 4 tests phylogenetic relationships among North American sphaeriid genera and, as a result, a sister relationship between Musculium and Sphaerium taxa is supported. The current taxonomy of the Sphaeriinae is revised based on separate as well as combined phylogenetic analyses of three different gene sequence data, mitochondrial COI and 16S, and nuclear ITS1 (Chapter 5). Five monophyletic lineages, Afropisidium, Cyclocalyx, Odhneripisidium, Pisidium and Sphaerium, are recognized within the subfamily instead of three cosmopolitan genera, Musculium, Sphaerium and Pisidium. Finally, Chapter 6 summarizes the results of all of these evolutionary studies. The results of these evolutionary studies not only increase our understanding of the phylogeny of the Sphaeriidae, but also provide valuable empirical data to assess polyploidy, a major topic in evolutionary biology.