Tau aggregates into neurofibrillary tangles in Alzheimer's disease and tauopathies. There is ongoing debate about whether tau aggregation is toxic and which form of tau is toxic. Based on recent studies showing that mature tau tangles can be dissociated from neuronal loss and cognitive deficits, it can be hypothesized that the intermediate pre-fibrillar tau aggregate is the predominant neurotoxic tau species. The toxicity of tau aggregation includes loss of physiological functions of native tau and gain of pathological functions of pre-fibrillar tau species. Mature tau tangles per se might be relatively inert or even represent failed cytoprotective efforts of protein quality control machineries in response to accumulating toxic tau species. Further studies on the mechanisms of tau aggregation, the structure of intermediate tau forms and their toxicity are needed to settle this debate.