Glycosphingolipids (GSL’s) are ubiquitous components of the cellular membranes of all eukaryotic cells, and nearly 300 different structures have been identified. 1 They are composed of at least one monosaccharide residue glycosidically linked to a hydrophobic ceramide or sphingoid long-chain aliphatic amino alcohol that is imbedded in the lipid bilayer. The presence of these molecules at the plasma membrane enriches the outer surface in a layer of carbohydrate that helps to protect the cell membrane from chemical and mechanical damage. Despite the relatively small contribution of glycosphingolipids to the mass of the lipid and protein components of the plasma membrane, several critical functions have been ascribed in vitro including cell adhesion, cell growth regulation, and differentiation. 2 Their importance in development has been demonstrated recently by the embryonic lethality in the mouse resulting from disruption of the gene encoding ceramide-specific glucosyltransferase, an enzyme that initiates the synthesis of all glycosphingolipids. 3 There is also a role played by glycosphingolipids in pathological processes where changes in the relative expression of these molecules at the cell surface follows oncogenic transformation. 4 The close proximity of glycosphingolipids to the lipid bilayer is exploited by a number of viral and bacterial pathogens that have adapted to adhere selectively to the carbohydrate residues as a prelude to internalization and pathogenesis. 5 When catabolism of glycosphingolipids is impaired, several severe pathological conditions in man are observed, 6 and although individually rare in incidence, it is a collectively significant and challenging group of disorders to treat. The incidence of glycolipid lysosomal storage disease has been estimated to occur at 1 in 18 000 live births worldwide and is the most frequent cause of pediatric neurodegenerative disease. This review describes some of the more recent knowledge of the enzymes involved in the control of glycosphingolipids biosynthesis and how catabolic deficiency leads to the glycosphingolipidoses. The emphasis is placed on how small-molecule inhibitors have been instrumental in probing the enzymes in these pathways and how their application has been taken from discovery in the laboratory to therapeutic use in man.