The characteristic O-linked glycosylation of the epidermal growth factor-like (EGF) domain was historically found in plasma proteins, but its importance has been recognized as it is involved in the structure and function of the EGF repeats of the Notch receptor [1]. As EGF domain-specific O-type glycans, three different glycan structures consisting of O-GlcNAc, O-fucose, and O-glucose are known. The corresponding glycosyltransferases have been identified, and the functional importance of EGF domain-specific O-type glycans has been established from the analysis of these knockout mice. Furthermore, genetic abnormalities in congenital diseases (Adams-Oliver syndrome, Dowling-Degos disease, limb-girdle muscular dystrophy) have also been revealed [2–5] (Table 86.1). Thus, understanding of the function of EGF domain glycans and their relationship with diseases is progressing.