The prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders that include scrapie in sheep, mad cow disease in cattle, and kuru, Creutzfeldt-Jakob disease, GSS disease and fatal familial insomnia in humans. Pathogenesis in these unusual diseases is associated with a conformational rearrangement of the cellular prion protein (PrPc) to an abnormal "scrapie" conformer, PrPSc. While the benign PrPc conformer is monomeric and rich in alpha-structure, PrPSc is a protein aggregate (often amyloid) characterized by an increased proportion of ß-structure and resistance to proteolytic digestion. Although molecular details of the pathogenic process in TSE diseases remain controversial, a growing body of evidence supports the protein-only model, according to which PrPSc itself is the infectious prion pathogen. PrPSc is believed to self-perpetuate by a unique mechanism involving binding to PrPc and inducing a conversion of the latter protein to the PrPSc state. The notion that an infectious agent can be devoid of nucleic acids and propagate by a mechanism based on self-perpetuating changes in protein conformation constitutes a new paradigm in molecular biology and medicine.