Chronic wasting disease (CWD) is an emergent, highly transmissible, geographically expanding, prion disease of both wild and captive cervids. CWD is unique among prion diseases in its facile contagion and environmental persistence. Its expanding geographical range, combined with the increasing transport of animals and animal products, portend its continued expansion and diversification. The zoonotic potential of CWD remains poorly understood. CWD endemic areas interface cervids with livestock species and humans, posing obvious zoonotic risks that over time will increase. While it is known that strains of CWD exist, nothing is known about the zoonotic potential of these strains. Work from our applicant group has shown that CWD infected cervids continually shed prions into the environment and that previously unrecognized environmental factors can influence the emergence of a dominant strain from a mixture. The ability to recognize the zoonotic potential of CWD strains is central to mitigating CWD transmission risk. The central hypothesis for work described here is that CWD strains evolve continuously due to a combination of both host and environmental factors. We will test this hypothesis by: i) determining the evolution and zoonotic impact of CWD strains in the native cervid species; ii) leveraging our unique animal resources, expertise, and in vivo & in vitro methodologies to assess environmental factors that alter CWD strain selection and evolution and iii) evaluate zoonotic potential of CWD strains by a complementary combination of in vitro amplification assays and animal transmission studies. The results will provide new information about this emergent transmissible prion disease and the risk it poses to humans and other species.