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The first tau transgenic mouse model was established more than a decade ago. Since then, much has been learned about the role of tau in Alzheimer's disease and related disorders. Animal models, both in vertebrates and invertebrates, were significantly improved and refined as a result of the identification of pathogenic mutations in Tau in human cases of frontotemporal dementia. They have been instrumental for dissecting the cross-talk between tau and the second hallmark lesion of Alzheimer's disease, the Aβ peptide-containing amyloid plaque. We discuss how the tau models have been used to unravel the pathophysiology of Alzheimer's disease, to search for disease modifiers and to develop novel treatment strategies. While tau has received less attention than Aβ, it is rapidly acquiring a more prominent position and the emerging view is one of a synergistic action of Aβ and tau in Alzheimer's disease. Moreover, the existence of a number of neurodegenerative diseases with tau pathology in the absence of extracellular deposits underscores the relevance of research on tau.