Transmissible spongiform encephalopathy (TSE) diseases, or prion diseases, are neurodegenerative diseases found in a number of mammals, including man. Although they are generally rare, TSEs are always fatal, and as of yet there are no practical therapeutic avenues to slow the course of disease. The epidemic of bovine spongiform encephalopathy (BSE) in the UK greatly increased the awareness of TSE diseases. Although it appears that BSE has not spread to North America, chronic wasting disease (CWD), a TSE found in cervids, is causing significant concern. Despite decades of investigation, the exact nature of the infectious agent of the TSEs is still controversial. Although many questions remain, substantial efforts have been made to understand the molecular features of TSE agents, with the hope of enhancing diagnosis and treatment of disease, as well as understanding the fundamental nature of the infectious agent itself. This review summarizes the current understanding of these molecular features, focusing on the role of the prion protein (PrP(c)) and its relationship to the disease-associated isoform (PrP(Sc)).