This article presents briefly current views on the role of prion protein (PrP) in Transmissible Spongiform Encephalopathies or prion diseases and the effect of PrP polymoryhisms on the susceptibility to these diseases, with special emphasis on sheep scrapie. The PrP genotype of sheep appears to be a major risk factor for scrapie, and polymorphisms at codons 136, 154, and 171 modulate the susceptibility of sheep for scrapie. Nevertheless, scrapie is not a spontaneous genetic disease alone. We describe an in vitro system in which sheep PrP variants show characteristics which reflect their linkage with in vivo scrapie susceptibility. Studies with this in vitro system not only confirm that scrapie susceptibility is determined by the PrP genotype of the target animal, but also suggest that the PrP genotype of the animal that is the source of the infectious agent plays an important role in determining scrapie susceptibility. The behaviour of PrP variants in this in vitro system may be an indicator for the transmissibility of prion diseases.