Several phosphorylation sites have been identified in tau proteins. Tau phosphorylation at different sites has a different impact on its biological function and on its pathogenic role. The normal level of tau phosphorylation is a consequence of dynamic regulation of tau kinases and tau phosphatases. The major tau kinases include glycogen-synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase 5 (cdk5), cAMP-dependent protein kinase (PKA), and stress-activated protein kinases. Among the protein phosphatases, PP2A is known to be an important one. Despite extensive studies, the causes leading to abnormal hyperphosphorylation of tau are still not fully understood. The hyperphosphorylation of the tau protein reduces its binding affinity to microtubules, thus disrupting the structural organization and maintenance. Excess levels of unbound tau protein leads to the formation of tau aggregates, insoluble fibrils, and intracellular neurofibrillary tangles observed in Alzheimer's disease (AD) and other tauopathies. In addition to hyperphosphorylation, alterations of tau itself, such as mutations in the MAPT gene, also plays a role in its aggregation.