Prions cause fatal, transmissible neurodegenerative diseases in animals and humans. These infectious agents are composed of misfolded versions of a host-encoded protein. Prions contain the necessary and sufficient information for propagation within their conformation, thus obviating requirements for agent-encoded genomic material. However, like nucleic acid containing pathogens, prions evolve to produce novel strains with unpredictable properties. The broad, long-term goals of our research are to understand the parameters controlling prion transmission and evolution within and between species, and ultimately to prevent recurrent epidemics in humans and animals. Chronic wasting disease (CWD), a burgeoning epidemic in cervids of increasingly uncertain zoonotic potential, is a particular focus within this general framework.