Transmissible spongiform encephalopathy (TSE) is a group of rare, sub-acute, fatal neurodegenerative diseases in humans and animals. TSE includes Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, fatal familial insomnia, and Kuru (a disease confined to the Fore linguistic group, a tribe in Papua-New Guinea). From the onset, it was recognized that some of these spongiform diseases occur in clusters, in an inherited, familial manner. This article describes these diseases, current treatment modalities, and suggests directions for future research.