The Transmissible Spongiform Encephalopathies (TSEs), such as scrapre, BSE, and Creutzfeldt-Jakob disease, are associated with alterations in the neural membrane protein or prion protein (PrP). This chapter will outline the gene targeting approaches that have been used to mutate the murine PrP gene, resulting in mice with reduction or absence of the PrP protein. It will then describe how these transgenuic animals can contribute to our understanding of the role of PrP in agent replication, the pathology of the TSEs, and the normal function of PrP