S. B. Prusiner proposed that the infectious agent of scrapie, the prion, is PrP^Sc, a modified form of the normal host protein PrP^c. Prn-p^0/0 mice devoid of PrP^c showed normal development and behavior. When inoculated with mouse scraple prions, they remained free of scrapie symptoms for at least 13 months while wild-type controls all died within 6 months. Surprisingly, heterozygous Prn-p^0/+ mice also showed enhanced resistance to scrapie. After introduction of Syrian hamster PrP transgenes, Prn-p^0/0 mice became highly susceptible to hamster but not to mouse prions. These experiments show that PrP^c, possibly at close to normal levels, is required for the usual susceptibility to scrapie and that lack of homology between incoming prions and the host's PrP genes retards disease.