O-GlcNAc is the attachment of β-N-acetylglucosamine to the hydroxyl group of serine and threonine in nuclear and cytoplasmic proteins. It is generally not further elongated but exists as a monosaccharide that can be rapidly added or removed. Thousands of proteins involved in gene transcription, protein translation, and degradation as well as the regulation of signal transduction contain O-GlcNAc. Brain is one of the tissues where O-GlcNAc is most highly expressed and deletion of neuronal O-GlcNAc leads to death early in development. O-GlcNAc is also important for normal adult brain function, where dynamic processes like learning and memory at least in part depend on the modification of specific proteins by O-GlcNAc. Conversely, too much or too little O-GlcNAc on other proteins participates in neurodegenerative processes underlying diseases such as Alzheimer’s and Parkinson’s. In this chapter, we describe the expression and regulation of O-GlcNAc in the nervous system.