The O-linked N-acetylglucosamine (O-GlcNAc) modification of several neuronal proteins has been identified. The identified proteins play a significant role in multiple neuropathologies, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis (ALS) and prion disease. Additionally, O-GlcNAc proteins are also implicated in synaptosomal transport and proteasome machinery that links it to multiple protein aggregates of neuronal disorders. More importantly, the two enzymes involved in O-GlcNAc dynamism, O-GlcNAc transferase and hydrolase, are both enriched in the brain, and genes encoding these two enzymes are frequently found in the regions of mutations of neurological diseases. This review highlights O-GlcNAc's role in neurological disorders and suggests future implications of the therapeutic modulation of O-GlcNAc.