The NMR structures of the recombinant cellular form of the prion proteins (PrP^C) of the cat (Felis catus), dog (Canis familiaris), and pig (Sus scrofa), and of two polymorphic forms of the prion protein from sheep (Ovis aries) are presented. In all of these species, PrP^C consists of an N-terminal flexibly extended tail with ≈100 amino acid residues and a C-terminal globular domain of ≈100 residues with three α-helices and a short antiparallel β-sheet. Although this global architecture coincides with the previously reported murine, Syrian hamster, bovine, and human PrP^C structures, there are local differences between the globular domains of the different species. Because the five newly determined PrP^C structures originate from species with widely different transmissible spongiform encephalopathy records, the present data indicate previously uncharacterized possible correlations between local features in PrP^C three-dimensional structures and susceptibility of different mammalian species to transmissible spongiform encephalopathies.