The subacute spongiform encephalopathies include scrapie of sheep, transmissible mink encephalopathy, and kuru and Creutzfeldt-Jakob disease of man. These diseases are caused by filterable infectious agents with unique physical properties. The usual sources of infection in nature are not completely known. Epidemiological evidence suggests that the agents may enter the body through breaks in the skin and mucous membranes. Experimental studies of scrapie after subcutaneous inoculation demonstrated early replication of the agent in lymphoid tissues and later appearance in other organs; as the amount of agent in the central nervous system (CNS) increased, it decreased in or disappeared from lymphoid tissues. In preliminary studies of kuru and Creutzfeldt-Jakob disease, the infectious agents were regularly recovered from the brains of clinically-ill patients and experimental animals but only occasionally from organs outside the CNS. It remains to be seen if early events in the pathogenesis of the two human diseases, before the appearance of clinical signs, are similar to those in scrapie.