Many neurodegenerative disorders with onset in mid to late adult life present diagnostic challenges to clinicians and pathologists alike. A distinguishing neuropathological feature has traditionally been the presence or absence of neurofibrillary tangles. Recent biochemical and molecular biological studies have identified the microtubule-binding protein tau as the predominant component of these and related inclusions, and have provided powerful new reagents for the study of neurodegenerative diseases. Several diseases previously considered distinct pathophysiological entities contain similar tau-immunoreactive lesions, but qualitative and regional anatomical differences in vulnerability can differentiate the disorders. Comparison of tau-immunoreactive lesions in three relatively uncommon neurodegenerative diseases-progressive supranuclear palsy, Pick's disease, and corticobasal degeneration-illustrates the types of analyses that demonstrate unexpected pathological similarities, but also fundamental differences between these disorders. These results have important implications for the differential diagnosis of disorders containing tau-immunoreactive lesions, including Alzheimer's disease.