Neurodegenerative tauopathies are marked by their common pathologic feature of aggregates formed of hyperphosphorylated tau protein, which are associated with synapse and neuronal loss. Changes in tau conformation result in both loss of normal function and gain of fibrillogenicity that leads to aggregation. Here, we discuss the pathophysiology of tau and emerging evidence of how changes in this protein might ultimately lead to neuronal death. In particular, based on recent evidence, we propose that a non-apoptotic caspase-associated form of death is occurring in tauopathy.