Natural scrapie in sheep occurs through a complex interplay between host genetic elements and various strains of the infectious scrapie agent. Scrapie-related polymorphisms in the coding region of the prion protein (PrP) gene, Prnp, have been studied in a number of breeds. The disease-promoting V136 allele, and the susceptibility-reducing R171 allele, have proved to be most important. However, variation in the coding region of Prnp cannot alone explain the diverse patterns of scrapie susceptibility in various breeds. For instance, in many breeds plagued with scrapie, the V136 allele appears to be a rarity. The R171 allele greatly reduces scrapie susceptibility This lays the molecular foundation for marker-assisted breeding for reduced scrapie susceptibility now underway in many countries. Although potentially important, and still under investigation, variable expression level and pattern of the ovine Prnp appears to be of little importance for the occurrence of natural scrapie. Studies of scrapie in mice also indicate that genetic elements other than Prnp may have a strong influence on scrapie incubation time, and hence susceptibility. Narrowing down the search to focus on these elements and identification of candidate genes are important tasks for future research in sheep scrapie.