Glycosylation – enabling genes are thought to comprise approximately 1-2 % of the human genome, thus, it is not surprising that more than 100 genetic disorders have been identified in this complex multi-pathway cellular process. Recent advances in next generation sequencing technology (NGS) have led to the discovery of genetic causes of many new disorders and importantly highlighted the broad phenotypes that occur. Here we will focus on two glycosylation pathways that involve lipids; glycosylphosphatidylinositol (GPI) anchors and glycosphingolipids (GSL) with emphasis on the specific gene defects, their biochemical properties, and their expanding clinical spectra. These disorders involve the intersection of two pathways: lipids and carbohydrates. Studies of both pathways were founded on structural biochemistry. Those methods and their more refined and sensitive descendants can both identify the specific genes that cause the disorders and validate the importance of the specific mutations.