The covalent addition of sugars to small organic molecules is mediated by a superfamily of UDP glycosyltransferases (UGTs) found in animals, plants and bacteria. This superfamily evolved by gene duplication and divergence to manage exposure to a changing environment of lipophilic chemicals. The recent characterization of the UGT3A family provides further insights into the origin and evolution of this superfamily in mammals and the role of individual UGTs in the formation of the various chemical glycosides found in body tissues and fluids. Furthermore, the unique UDP-sugar specificities of the two enzymes in this family inform our knowledge of UGT structure relating to catalysis and UDP-sugar specificity. In addition to the UGT3 gene family, three other gene families, UGTs1, 2, and 8, are found in mammalian genomes. The 19 members of the UGT1 and 2 families have a major role in processing lipophilic chemicals due to their capacity to glucuronidate a broad range of structurally-dissimilar substrates. In contrast, the UGT3 enzymes only have a minor role, as their activities are very low in the major drug-metabolic organs, and their N-acetylglucosaminide and glucoside products are only a minor component of circulating and excreted drug metabolites. Although the endogenous role of the UGT3 family is still unknown, participation in the processing of lipophilic chemicals in specific cell types or at specific times during ontogeny cannot be excluded. In contrast to the UGT 1, 2 and 3 families, the single member of the UGT8 family appears to have no role in drug metabolism.