The term prion disease describes a group of fatal neurodegenerative diseases that are believed to be caused by the pathogenic misfolding of a host cell protein, PrP. Susceptibility to prion disease differs between species and incubation periods before symptom onset can change dramatically when infectious prion strains are transmitted between species. This effect is referred to as the species or transmission barrier. Prion strains represent different structures of PrPSc and the conformational selection model proposes that the source of theses barriers is the preferential incorporation of PrP from a given species into only a subset of PrPSc structures of another species. The basis of this preferential incorporation is predicted to reside in subtle structural differences in PrP from varying species. The overall fold of PrP is highly conserved among species, but small differences in the amino acid sequence give rise to structural variability. In particular, the loop between the second beta-strand and the second alpha-helix has shown structural variability between species, with loop mobility correlating with resistance to prion disease. Single amino acid polymorphisms in PrP within a species can also affect prion susceptibility, but do not appear to drastically alter the biophysical properties of the native form. These polymorphisms affect the propensity of self-association, in recombinant PrP, to form beta-sheet enriched, oligomeric, and amyloid-like forms. These results indicate that the major factor in determining susceptibility to prion disease is the ability of PrP to adopt these misfolded forms by promoting conformational change and self association.