Transmissible spongiform encephalopathies have a long and still unfinished history replete with spectacular discoveries and equally spectacular failures. The story begins in the 18th century with the first descriptions of scrapie, a naturally contagious disease of sheep that was not experimentally proven to be a transmissible infection until 1936. This discovery permitted veterinarian investigators to begin to explore aspects of pathogenesis and the nature of the infectious agent. The additional discovery, in the 1960's, that scrapie was similar to the human diseases kuru and Creutzfeldt-Jakob vastly widened what had been a comparatively restricted field of research, and led to rapid advances in molecular characterization of the disease agents, culminating in the proposal that they are self-replicating abnormally configured host proteins, or "prions". Despite these advances, we have seen in recent years 3 potentially preventable outbreaks of disease: iatrogenic Creutzfeldt-Jakob disease due to contaminated pituitary hormone extracts and dura mater grafts, and a new variant of the disease (Will-Ironside syndrome) linked to consumption of beef contaminated by the agent of bovine spongiform encephalopathy, underscoring the disparity between fundamental knowledge and its practical application.