Transmissible spongiform encephalopathies (TSEs) are caused by infectious agents with stable virulence characteristics that are not encoded by the host. Agent-specific features of virulence include variable disease latency and tissue pathology in a given host, as well as the ability to spread to many species. Such cross-species infections contradict predictions based on the prion hypothesis. Recent transmissions of several human agents to normal mice and to monotypic neural cells in culture, underscore the existence of unique agent clades that are prevalent in particular geographic regions. Examples include the epidemic UK bovine agent (BSE) and the New Guinea kuru agent. The virus-like biology of unique TSE agents, including epidemic spread, mutation, and superinfection, can be used to systematically define features of virulence that distinguish common endemic from newly emerging strains.