Enriching fractions from Syrian hamster (SHa) brain for scrapie prion infectivity led to the discovery of the prion protein (PrP). Prion diseases include scrapie of sheep, bovine spongiform encephalopathy (BSE) of cattle, as well as Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familial insomnia (FFI) of humans. Discovery of mutations in the PrP genes of humans with familial CJD, GSS, and FFI established that prion diseases are both genetic and infectious. Many lines of evidence have converged to argue that infectious prions are composed largely, if not entirely, of PrPSc molecules. Mice overexpressing mutant and wild-type transgenes develop neurologic illnesses spontaneously and produce prions as demonstrated by serial transmission of disease in rodents after inoculation of brain extracts. Although these and many other findings argue that prions are devoid of nucleic acid, the molecular basis of prion strains remains enigmatic. The formation of PrPSc from PrPC is a posttranslational process involving the conversion of alpha-helices into beta-sheets. This conformational change in PrP appears to be the fundamental event that underlies prion propagation and the pathogenesis of prion diseases. The unique features of prion structure and propagation differentiate prions from all other transmissible pathogens.