Publisher Summary Bacteroides fragilis are common colonic commensals comprising about 0.1% of the fecal flora in the majority, if not all, humans. Despite their small numbers in the fecal flora, B. fragilis are the leading anaerobes in intraabdominal and bloodstream infections. Although the extraintestinal virulence of B. fragilis has long been ascribed to the capsule of the organism recent data has begun to highlight both the genetic and molecular diversity of B. fragilis with the recognition that the organism expresses at least eight distinct capsular polysaccharides. This chapter summarizes the progress that has occurred over the last 20 years in understanding the genetics and mechanism of action of BFT. The cleavage of E-cadherin by BFTs represents the first time that E-cadherin has been described as a bacterial toxin substrate. In addition, BFT is the first cytoskeletal-altering toxin predicted to act solely at the cell surface and without covalent enzymic modification of an intracellular substrate. Remodeling of cell-surface proteins by extracellular proteases is a mechanism yielding specific cellular responses and triggering specific cellular signal transduction pathways. Future studies to identify the mechanisms by which BFT induces cellular proliferation, inflammation, and actin cytoskeletal rearrangement are expected to contribute to the understanding of both normal and pathologic cell function. Importantly, the ability of BFT to induce cellular proliferation and inflammation suggests the hypothesis that prolonged mucosal colonization with ETBF may contribute to the pathogenesis of intestinal inflammatory and oncogenic processes.