The aims of this thesis were to determine the importance of draining lymphoid tissue in the pathogenesis of the ME7 strain of scrapie agent after inoculation via the oral, scarification or intra-peritoneal (i.p.) routes. The formation of most lymphoid tissue is critically dependent on lymphotoxin (LT) αβ signalling through LTβR during gestation. Mice in which this signalling has been interrupted lack various lymphoid tissues. After oral inoculation Peyer’s patches (PPs) within the intestine were found to be crucial for pathogenesis as mice lacking PPs did not develop disease. Isolated lymphoid follicles (ILFs) have recently been described in the murine small intestine and are thought to compensate for PP deficiency. ILFs were found to contain FDCs and support neuroinvasion of the scrapie agent in the absence of PPs. Mice lacking inguinal lymph nodes (ILNs) displayed decreased susceptibility to scrapie disease after inoculation via scarification of the skin of the thigh. This demonstrated that the ILNs are important, but neuroinvasion could occur from other tissues in some cases. The parathymic lymph nodes (ptLNs) drain the peritoneal cavity.   LTα^-/- mice and LTβ^-/- mice lack these nodes. LTα^-/- mice were less susceptible and had delayed onset of disease compared to WT mice whereas LTβ^-/- mice were as susceptible and developed disease in the same time frame as WT mice after i.p. inoculation. This demonstrated that the ptLNs are dispensable for neuroinvasion via the i.p. route, but raised the possibility that lymphoid tissue present in LTβ^-/- mice and absent from LTα^-/- mice was important in supporting neuroinvasion. In all three routes the lack of draining lymphoid tissue had an effect on the pathogenesis of disease demonstrating the importance of these tissues in the peripheral pathogenesis of TSEs.