N-Linked glycosylation (N-glycosylation) of proteins has long been associated with oncogenesis, but not until recently have the molecular mechanisms underlying this relationship begun to be unraveled. Here, we review studies describing how dysregulation of the N-glycosylation-regulating gene, DPAGT1, drives oral cancer. DPAGT1 encodes the first and rate-limiting enzyme in the assembly of the lipid-linked oligosaccharide precursor in the endoplasmic reticulum and thus mediates N-glycosylation of many cancer-related proteins. DPAGT1 controls N-glycosylation of E-cadherin, the major epithelial cell–cell adhesion receptor and a tumor suppressor, thereby affecting intercellular adhesion and cytoskeletal dynamics. DPAGT1 also regulates and is regulated by Wnt/β-catenin signaling, impacting the balance between proliferation and adhesion in homeostatic tissues. Thus, aberrant induction of DPAGT1 promotes a positive feedback network with Wnt/β-catenin that represses E-cadherin-based adhesion and drives tumorigenic phenotypes. Further, modification of receptor tyrosine kinases (RTKs) with N-glycans is known to control their surface presentation via the galectin lattice, and thus increased DPAGT1 expression likely contributes to abnormal activation of RTKs in oral cancer. Collectively, these studies suggest that dysregulation of the DPAGT1/Wnt/E-cadherin network underlies the etiology and pathogenesis of oral cancer.