Publisher Summary Glycosphingolipids (GSL) are ubiquitous membrane components located almost exclusively at the outer leaflet of the plasma membrane of mammalian cells. All GSLs share a common hydrophobic backbone dipped in the membrane—that is, ceramide (Cer) that consists of a fatty acid chain linked to the sphingosine base. In contrast, the hydrophilic oligosaccharide residues of GSL protrude into the extracellular space. GSL are classified into three main series—that is, ganglio, globo, and lacto, according to their carbohydrate structure, which may include one of 200 different oligosaccharides. Ideally, the design of synthetic soluble analogs of glycolipids may preserve the biologically active conformation of the carbohydrate part of the GSL while increasing the polarity of the ceramide moiety to improve solubility in water. The latter can be done, for instance, by omitting the fatty acid chain or by adding a polar group such as carboxylate at the end of the ceramide-like hydrophobic chains. Synthetic analogs with a very short hydrophobic domain may be present as monomers in aqueous solution. The gain in solubility may be correlated with a total lack of antiviral activity, as these compounds may not aggregate in water. On the opposite, synthetic analogs with a large hydrophobic part may be almost insoluble in water. The biological activity of such analogs should be tested after incorporation of the molecule in liposomes, which may increase the background values of the solid-phase assays described in this chapter. For the same reasons, the addition of organic solvents to facilitate the solubilization of synthetic GSL analogs is not indicated.