Peyer’s patches (PPs), part of the gut-associated lymphoid tissue (GALT), may represent a portal of entry for orally transmitted prions and appear to be the most likely sites of prion accumulation in the gastrointestinal tract. The main aim of this project was to determine whether the observed age-susceptibility relationship of scrapie, BSE and vCJD could be explained by the development of PPs in the gut. PP tissue was quantified in the distal ileum of NPU Cheviot sheep, and data on measures of PP development in cattle and humans were extracted from previous studies. Because follicular dendritic cells (FDCs) have been implicated as the likely sites of prion replication in lymphoid tissues, Immunocytochemistry was carried out to investigate the ontogeny of PrP-associated FDCs in ileal PP tissue in both mice and sheep. Results showed that age at exposure to the TSE agent is a potentially important factor in determining disease outcome as well as the incubation period of disease. Younger sheep were found to have shorter incubation periods than older animals following subcutaneous inoculation of the infectious agent. For sheep, cattle and humans, measures of PP development peaked in adolescent years. There was a significant correlation between measures of PP development and estimated risks of TSE infection. PrP-associated FDCs can first be detected in 7 day-old mice, and provided further evidence for the presence of mature FDC networks in GALT of postnatal sheep. In the absence of FDCs, mice younger than 7 days old may be less susceptible to oral scrapie challenge. The presence of FDCs in newborn sheep suggest that these animals may be susceptible to TSE infection in early postnatal life particularly at lambing when an infected placenta could act as a source of scrapie infection to the young lamb.