The structural diversity of the human glycome is vast and poses challenges for exploring biological functions and dissecting specific structure-function relationships. The true functional diversity of the glycome is, however, predicted to be lower when grouping structures with common or repeated features. The human glycome is orchestrated by over 200 distinct glycosyltransferase genes, and our knowledge of the properties of these and their roles in known glycosylation pathways in cells is relatively advanced. Currently some 170 glycosyltransferase genes can be assigned to rather specific roles in biosynthetic steps for the human glycome, although for many of the isoenzyme families our understanding of the unique functions of individual enzymes is limited. Current knowledge of assembly of the human glycome suggests that it is simpler to explore and dissect the glycome by a genetic entry point rather than from a structural entry point. Emergence of nuclease-based gene-editing tools enabling highly specific and facile knockout and site-directed knockin of glycosylation-related genes have led to wide use of the genetic approach to glycomics and new tools for the field. Our group has extensively adopted the genetic approach for dissection and discovery of biological functions of protein glycosylation, and explored the options for custom design of glycosylation of recombinant glycoprotein therapeutics as well as using cell libraries for display of the glycome. An overview of these efforts will be presented.