Sugar nucleotides play a critical role in biology due to their role as substrates for glycosyltransferase enzymes, which are ubiquitous throughout biology and involved in a variety of essential processes which include energy storage, carbohydrate metabolism, intra- and extracellular trafficking and recognition, protein glycosylation, cell wall biosynthesis, and the synthesis of medicinally relevant natural products. The study and application of glycosyltransferases in the biosynthesis of natural products and drug discovery efforts and, indeed, the role of glycosylation in biology in general, continue to be limited by both the lack of glycosyltransferases promiscuous in terms of both nucleotide sugar and aglycon recognition and easily accessible routes to sugar nucleotides. The Streptomyces antibioticus glycosyltransferase OleD, however, provides an excellent model system for both understanding general promiscuity and catalyzing formation of nucleotide sugars through application of underutilized reverse reactions. OleD and its engineered variants are capable of serving as general catalysts for drug discovery efforts by recognizing over 70 unique aglycon scaffolds, afford facile access to over 40 unique natural and ‘unnatural’ nucleotide sugars in a combinatorial manner, serve as a model with which to understand and exploit the typical thermodynamic landscape of these reactions, and provide high throughput colorimetric assays for general glycosyl transfer and sugar nucleotide utilization. These discoveries and technology developments are directly applicable to drug discovery, protein engineering, and other sugar nucleotide dependent investigations and promise to inspire future efforts into understanding and harnessing glycosylation’s unique role in biology.