Tau is a neuronal microtubule-associated protein found predominantly on axons that functions to promote tubulin polymerization and stabilize microtubules. Tau, in its hyperphosphorylated form, is the major component of paired helical filaments (PHF), the building block of neurofibrillary lesions in Alzheimer’s disease (AD) brain. Hyperphosphorylated tau is also found in neurofibrillary lesions in a range of other central nervous system disorders. Hyperphosphorylation impairs the microtubule binding function of tau, resulting in the destabilization of microtubules in AD brains, ultimately leading to the degeneration of the affected neurons. Numerous serine/threonine kinases including GSK-3beta, protein kinase A (PKA), cyclin-dependent kinase 5 (cdk5) and casein kinase II, phosphorylate tau. Serine 404 is phosphorylated by GSK-3beta and cdk5 in vitro and in vivo.