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Publisher Summary Many bacteria choose host cell carbohydrates as their initial means to interact with their eukaryotic target cells. While such cells are normally surrounded by a candy coat to provide an entree for a broad prokaryotic diet, bacterial toxins can have an exquisitely glycosphingolipid (GSL)-selective palate. The three most significant bacterial subunit toxins, including cholera toxin (CT), Shiga toxin (Stx), and verotoxin (VT), share the property of GSL receptor binding. These three A1B5-subunit toxins are considered in this chapter. The binding of the pentameric B-subunits of cholera toxin and verotoxin to GM1 ganglioside and globotriaosyl ceramide (Gb3), respectively, initiates the process of internalization and intracellular trafficking of the A-subunit to the endoplasmic recticulum for cytosolic translocation. The diseases that can subsequently occur, i.e., dysentery and hemolytic uremic syndrome, respectively, depend on the organ distribution of these GSLs and the catalytic activity of the A-subunit, in other words, the ability of adenosine diphosphate ribosyl transferase to activate chloride transport/water efflux and protein synthesis inhibition via depurination of the 60S ribosomal subunit, respectively. Both toxins require the GSL receptor to be present in detergent-resistant domains for cytopathology. In each case, GSL receptor binding initiates a transmembrane signaling cascade, despite the fact that GSLs are not transmembrane components. The cholera toxin B-subunit provides a powerful tool in modulation of the immune system and verotoxin 1 (VT1) provides insight into the relationship between cell drug resistance and GSL metabolism, Gb3 expression and cancer, and the link between Gb3 and human immunodeficiency virus susceptibility.