The neuropathological diagnosis of Alzheimer's disease relies on the presence of both neurofibrillary tangles and senile plaques. The number of neurofibrillary tangles is tightly linked to the degree of dementia, suggesting that the formation of neurofibrillary tangles more directly correlates with neuronal dysfunction. The regional pattern of areas affected by neurofibrillary tangles formation during the course of the disease is relatively stereotyped. Neurofibrillary tangles are composed of highly phosphorylated forms of the microtubule-associated protein tau. Phosphorylated tau proteins accumulate early in neurons, even before formation of neurofibrillary tangles, suggesting that an imbalance between the activities of protein kinases and phosphatases acting on tau is an early phenomenon. The latter might be related to changes in signalling through transduction cascades, since many of the protein kinases generating phosphorylated tau species participate in signalling pathways. The accumulation of neurofibrillary tangles and phosphorylated tau species is associated with disturbances of the microtubule network and, as a consequence of the latter, of axoplasmic flows. The mechanistic relationship between the formation of neurofibrillary tangles and senile plaques is still little understood and in vivo formation of neurofibrillary tangles in experimental models has not yet been achieved. Future animal models, e.g. transgenic animals expressing combined key human proteins, will hopefully reproduce faithfully all the major cellular lesions of the disease.