O-GlcNAc dynamics play extensive roles in epigenetic regulation, development, and cancer. The Hexosamine Biosynthetic Pathway acts at the macronutrient level to produce UDP-GlcNAc. Nucleocytoplasmic OGT modifies transcription factors, chromatin remodeling proteins, RNA polymerase II, and splicing factors for extensive nutrient/stress-responsive epigenetic events. In development, stem cells use these programs to differentiate. Numerous cancers harness enhanced HBP flux to activate growth, survival, and metastatic programs through balancing differentiation and de-differentiation to cancer stem cells.