Brain damage in the transmissible spongiform encephalopathies or prion diseases is associated with the conversion of normal host prion protein to an abnormal protease-resistant isoform, and expression of prion protein is required for susceptibility to these diseases. This article reviews the data on studies using transgenic mice expressing prion protein in specific individual cell types to study the roles of these cell types in prion disease pathogenesis. Surprisingly damage to neurons in brain and retina appeared to require different prion protein-expressing cells, suggesting that different pathogenic mechanisms operate in these two neuronal tissues.