Publisher Summary This chapter describes that neurofibrillary tangles (NFT) are, with senile plaques, the hallmark neuropathological lesions used for the neuropathological diagnosis of Alzheimer's disease. The intensity of these lesions, particularly NFT, is correlated with the severity of the dementing syndrome. NFT are constituted of bundles of abnormal filaments, called paired helical filaments (PHF), accumulating in neurons in this disease. NFT are also a key lesion of other neurodegenerative diseases, such as frontotemporal dementias (FTD), corticobasal degeneration, Pick's disease, and progressive supranuclear palsy. Many different models of cellular lesions found in tauopathies are now available. Most convincing models highlight the role of tau hyperphosphorylation in neurodegeneration as an essential aspect of NFT formation. In models developing NFT, the brain distribution of these lesions is variable, and might not reflect the exact topography of brain lesions in human diseases. The reproduction of NFT formation in animal models will help in the analysis of neuronal dysfunction linked to these neuronal lesions common to several neurodegenerative diseases.