Hundreds post-translational modifications (PTM) were characterized among which a large variety of glycosylations including O-GlcNAcylation. Since its discovery, O-GlcNAcylation has emerged as an unavoidable PTM widespread in the living beings including animal and plant cells, protists, bacteria and viruses. In opposition to N- and O-glycosylations, O-GlcNAcylation only consists in the transfer of a single N-acetylglucosamine moiety through a beta-linkage onto serine and threonine residues of proteins confined within the cytosol, the nucleus and the mitochondria. The O-GlcNAc group is provided by UDP-GlcNAc, the end-product of the hexosamine biosynthetic pathway located at the crossroad of cell metabolisms making O-GlcNAcylation a PTM which level tightly reflects nutritional status; therefore regulation of cell homeostasis should be intimately correlated to lifestyle and environment. Like phosphorylation, with which it can compete, O-GlcNAcylation is reversible. This versatility is managed by OGT (O-GlcNAc transferase) that transfers the GlcNAc group and OGA (O-GlcNAcase) that removes it. Also, like its unsweetened counterpart, O-GlcNAcylation controls fundamental processes, e.g. protein fate, chromatin topology, DNA demethylation and, as recently revealed, |