Since its discovery as a structural component of neurofibrillary lesions of Alzheimer's disease more than twenty years ago, tau protein has been implicated in the cascade of events associated with neurodegeneration. Specifically, the "tau hypothesis" posits that misfunction of tau, which occurs in response to unknown stimuli, results in its intracellular assembly into filaments that eventually prove toxic to the cells that produce them. The tau hypothesis is supported by numerous neuropathological and genetic observations of authentic human disease cases. However, experiments designed to study aggregate toxicity in biological models suggest that some aggregate species may be inert or could potentially serve a neuroprotective function. Distinguishing these possibilities experimentally has been complicated by currently available biological models, which do not fully recapitulate aggregation conditions seen in disease. Additional model systems which better approximate physiological conditions may help elucidate the molecular mechanisms involved in aggregation associated toxicity. Here we examine the accumulated evidence linking aggregation and neurodegeneration, and experimental approaches to the problem of tau aggregation-mediated toxicity.