The prion diseases, or transmissible spongiform encephalopathies (TSEs), are a family of rare transmissible and familial diseases in humans and other animals which invariably lead to a protracted course of neurologic signs and ultimately death. Increased interest in these diseases has developed in the last decade after the emergence of bovine spongiform encephalopathy (BSE) or “mad cow disease” in the United Kingdom. Chronic wasting disease (CWD) is the only prion disease known to affect free-ranging wildlife worldwide. In the endemic areas of Colorado and Wyoming, up to 15% of free-ranging mule deer are infected and the potential of CWD transmission to livestock or humans is unknown. Extensive surveillance of hunter-killed deer and elk over the past five years has revealed that the disease reaches up to 15% prevalence in wild deer, higher than ever reported for BSE. How does transmission occur in these free-ranging populations of herbivores? Why is the prevalence so high compared to the other TSEs? Which species are susceptible to CWD? What is the most efficacious way to manage this disease in free-ranging cervid populations? How can we diagnose the disease ante-mortem? Many important and intriguing questions remain to be addressed.