Publisher Summary PrP associated with TSE disease (PrP-res) can induce its own formation, an essential prerequisite for a protein-only infectious agent. This “replication” is clearly influenced by prion protein (PrP) primary sequence and conformation. Supporting data are now available for how, in the absence of any nucleic acid component, these variations in PrP sequence and conformation could account for TSE species and strain characteristics. As a transmissible neurodegenerative disease, involving protein misfolding and amyloid formation, the TSE diseases are undoubtedly biologically unique. The question remains whether PrP-res alone can directly dictate all aspects of TSE pathogenesis or whether as yet unidentified factors or more conventional viral components are also involved.