The presence of abundant neurofibrillary lesions made of hyperphosphorylated tau proteins is the characteristic neuropathology of a subset of neurodegenerative disorders classified as "tauopathies." The discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. Moreover, it now is known that the most common form of sporadic frontotemporal dementia (FTD), which is characterized by frontotemporal neuron loss, gliosis, and microvacuolar change, also is a tauopathy caused by a loss of tau protein expression. Thus, these discoveries have begun to change the classification and the neuropathologic diagnosis of FTD and tauopathies, as well as current understanding of the disease mechanisms underlying them. Although transgenic mice expressing wild-type human tau or variants thereof with an FTDP-17 mutation result in tau pathologies and brain degeneration similar to that seen in human tauopathies, the precise mechanisms leading to the onset and progression of neurodegenerative disorders remain incompletely understood. Here, we review current understanding of human neurodegenerative tauopathies and prospects for translative recent insights about these into therapeutic interventions to prevent or ameliorate them.