From April 2005, member states of the European Union were required to implement a compulsory breeding programme for resistance to transmissible spongiform encephalopathies (TSEs) in sheep as part of measures to eradicate TSEs from national flocks. In this paper, we assessed the impact of four different breeding strategies on prion protein (PrP) genotype frequencies using a mathematical model which describes in detail gene flow in the British sheep flock. These strategies ranged from the minimum requirements laid down in by EU legislation to compulsory implementation of the current National Scrapie Plan for Great Britain (NSP) ram genotyping scheme. All four strategies were predicted to substantially reduce the frequency of the VRQ allele, which is associated with the highest risk of scrapie, although schemes with more stringent requirements produced a larger reduction. However, there were marked differences in the impact of the strategies on the frequency of other PrP alleles. In particular, restrictions beyond those required by EU legislation were necessary to change the frequency of other PrP alleles substantially. Consequently, a breeding programme which aims to reduce the risk to human health by reducing the frequency of the ARQ allele (associated with the highest risk of BSE in sheep) must place restrictions on ARQ-bearing animals. Similarly, a programme which seeks to increase the frequency of the ARR allele (associated with the lowest risk of TSE) must favour ARR-bearing animals.