Transmissible spongiform encephalopathies (TSE) are a group of infectious diseases caused by a misfolded protein. Naturally occurring TSEs are found in numerous species including sheep, cattle, and mink. The naturally occurring TSE of sheep is called scrapie. Scrapie is one of the oldest described TSEs, and it is caused by a misfolded protein (PrPSc) that initiates an autocatalytic conversion of an endogenous host protein (PrPC). The mammalian PRNP gene encodes PrPC, and sheep are variably susceptible to disease based on naturally occurring polymorphisms in the PRNP gene at codons 136, 154, and 171. The selection of resistant genotypes is essential to scrapie eradication programs. Currently there are polymorphisms in some breeds of sheep that have not been thoroughly investigated vis-à-vis their contribution to scrapie susceptibility. Herein we describe the contribution of lysine at codon 171 (K171) of the PRNP gene towards resistance to classical scrapie. Using sheep, the natural host, as model to evaluate genetic susceptibility, we experimentally infected sheep with different allelic polymorphisms at codon 171. Orally inoculated sheep with the homozygous lysine 171 (KK171) genotype did not develop scrapie or harbor any detectable PrPSc. In the second study encompassing this work, we sought to evaluate the etiology of transmissible mink encephalopathy (TME), a naturally occurring TSE of mink. TME is a foodborne TSE of farmed mink, and earlier theories suggested that classical scrapie or atypical BSE may have been the source of prions to mink. The etiology of prion diseases is best understood by experimental transmission between species. To determine if scrapie is the source of TME, we examined the susceptibility and disease phenotype of sheep inoculated with the TME agent. We determined that only intracranially inoculated sheep are susceptible, and the disease phenotype in sheep is different from classical scrapie. Primarily, sheep inoculated with the TME agent do not develop immunoreactivity for PrPSc in their lymphoid tissue; whereas, it is known that sheep with classical scrapie have prominent lymphoid accumulation of PrPSc. Cumulatively, this research expands the current knowledge of ovine genetic susceptibility to scrapie and indicates that classical scrapie is not likely to be the source of TME. Practically, the knowledge presented in this work is immediately applicable to designing or updating genotype-based scrapie eradication plans.