Scrapie resistance and susceptibility in sheep are genetically controlled. The occurrence of natural and experimental scrapie has been linked to polymorphisms of the sheep’s prion protein (PrP) gene at position 136 (V-A), 154 (R-H) and 171 (Q-R-H). The ovine alleles VRQ and ARQ seem to be related to a higher susceptibility, while the alleles ARR and AHQ coincide with a low susceptibility to scrapie infection. Selection of sheep with scrapie-resistant genotypes (ARR/ARR) is currently one of the most important objectives of the sheep breeding associations. During the last 2 years, however, new data has become available relating to TSE cases in TSE-resistant sheep in several EU member states, including the Nor98 strain and other atypical TSE cases carrying the ARR allele. However, these findings could have major implications for the national breeding programs in several EU member states. The present paper describes the second natural atypical TSE case in a sheep with a scrapie-resistant genotype (ARR/ARQ) detected via active surveillance in Belgium, in addition to the previously detected ARR/ARR case. The Western Blot pattern of both sheep corresponds with that of the Nor98 strain. The continued appearance of new “atypical” TSE cases in sheep with scrapie-resistant genotypes undermines the purpose and efficacy of the breeding programs.