Prion diseases (spongiform encephalopathies) in humans are Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and kuru. Clinically, they are characterized by an inexorably progressing neurological illness with dementia and ataxia as the most prominent signs. The classical neuropathological changes are limited to the central nervous system and consist of spongiform degeneration, amyloid plaques, astrocytic gliosis, and nerve cell loss. The human spongiform encephalopathies, which for many years were considered neurodegenerative disorders of unknown etiology, were finally recognized as transmissible diseases similar to scrapie in sheep in the late 1960's. The infectious agent appears to consist of protein devoid of functional nucleic acid and has been termed prion to distinguish it from viruses. The prion hypothesis has gained wide acceptance through the finding that mutations of the prion protein gene are associated with heritable human prion disease. Different mutations appear to cause prion disease with a distinct pattern of clinical and pathological features in a great number of families. Certain mutations of the PrP gene have been shown to be associated with clinical and neuropathological changes not typical of any variant of human prion disease known to date. A new classification of prion diseases based on the molecular biology and biochemistry of the prion protein is likely to emerge.