O-GlcNAcylation has emerged as a critical post-translational modification important for a wide array of cellular processes. This modification has been identified on a large pool of intracellular proteins that have wide-ranging roles, including transcriptional regulation, cell cycle progression, and signaling, among others. Interestingly, in mammals the single gene encoding O-GlcNAc Transferase (OGT) is located on the X-chromosome near the Xist locus suggesting that tight dosage regulation is necessary for normal development. Herein, we highlight the importance of OGT dosage and consider how its genomic location can contribute to a gender-specific increased risk for a number of diseases. Published by Elsevier Inc.