The species barrier in prion infectivity is believed to reside in the degree of amino acid sequence heterology between the infectious prion protein, PrP(Sc), of the donor and the normal PrP of the host. bring new evidence that distinct PrP(Sc) species or prion strains may have different conformations even when they have identical amino acid sequence and that the conformation of the exogenous prion strain is a determinant of the species barrier in hosts that have identical PrP genotype.