To understand the profound influence of common polymorphisms at residue 129 [6, 7, 183], the rare polymorphism at residue 127 [9] and residue 219 [66] of the PRNP gene in susceptibility to acquired, sporadic and some inherited prion diseases and association of different polymorphisms with certain prion strains, transgenic, and knock-in humanised mouse models have been of particular importance. This evidence concerns the gene PRNP and prion disease.