Resistance to transmissible spongiform encephalopathies (TSEs) in sheep can be influenced by polymorphisms of the gene that encodes prion protein (PrP). In vitro conversion experiments showed that VRQ and ARQ alleles of PrP are associated with susceptibility to bovine spongiform encephalopathies (BSE), whereas the ARR allele is associated with resistance to the conversion of PrP to the disease-causing PrP^Sc form. But in the May 29 Nature, Fiona Houston and colleagues from Institute for Animal Health show that even the sheep with the genotype associated with highest resistance (ARR) can still be infected with BSE by intracerebral inoculation (Nature, 423:498, May 29, 2003).