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O-GlcNAcylation was identified in the 1980s by Torres and Hart (1) and modifies thousands of cellular proteins, yet the regulatory role of O-GlcNAc is still poorly understood compared to the abundance of mechanistic information known for other cycling post-translational modifications like phosphorylation. Many challenges are associated with studying O-GlcNAcylation and are tied to the technical hurdles with analysis by mass spectrometry. Over the years, many research groups have developed important methods to study O-GlcNAcylation revealing its role in the cell, and this perspective aims to review the challenges and innovations around O-GlcNAc research and chronicle the work by Donald F. Hunt and his laboratory, particularly in development of ETD and its application to this field of research.