Abstract: A major focus of current experimental therapies for neurodegenerative diseases is on modulating post-translational modifications (PTMs) of the microtubule-associated protein tau. Tau is a highly soluble, neuronal protein that is comprised of four domains – the N-terminal projection domain, the proline-rich region, the microtubule-binding domain, and the C-terminal tail. As a scaffold protein, tau dynamically interacts with numerous structural and functional biomolecules, such as cytoskeleton and motor proteins, chaperones, enzymes, DNA, RNA, and lipids. Over a dozen types of PTMs, combined with alternative splicing, confer upon tau its enormous structural heterogeneity, which subserves its many (patho-)physiological functions.