Transmissible spongiform encephalopathies are fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy and scrapie in sheep and goats. Transmissible spongiform encephalopathies are thought by some to result from changes in the conformation of a membrane glycoprotein called PrPC (prion protein) into a pathogenic form, PrPSc, which constitutes the major component of an unprecedented type of infectious particle supposedly devoid of nucleic acid. Although there is no primary immunological response to the infectious agent, several lines of evidence indicate an involvement of the lymphoreticular system in the development of prion diseases. Studies in rodents have shown that after peripheral infection, uptake of the scrapie agent is followed by an initial phase of replication in the lymphoreticular system, particularly the spleen and lymph nodes. Moreover, infectivity titers in lymphoreticular organs reach a maximum relatively quickly, well before those in the brain, and then maintain a plateau for the remainder of the disease progression. The presence of PrPSc in peripheral lymphoid organs of all cases of variant Creutzfeldt-Jakob disease strongly underscores the importance of the lymphoreticular system. Thus, a better understanding of the cells participating in PrPSc replication and dissemination into the central nervous system is of particular interest. This review will therefore discuss the present knowledge of the role of the spleen in transmissible spongiform encephalopathies as well as the participation of the different spleen cell types in the disease process.