Prion diseases or transmissible spongiform encephalopathies are lethal neurodegenerative diseases caused by proteinaceous agents that consist of an abnormal form of a host protein designated PrP and are devoid of nucleic acids. In laboratory settings these diseases are usually transmitted by intracerebral or peripheral inoculation. In the field they have been shown to be transmitted by uptake of contaminated food but in most instances the route of transmission remains obscure. Both nervous and lymphatic tissues in peripheral organs have been implicated in the spread and propagation of prions. The exact sites of uptake and initial propagation of the infectious agents have not yet been determined, however. As the expression of PrPc is required for the propagation of the infectious agent the search for peripheral cells positive for PrPc may reveal potential routes of entry and transmission. Recently epidermal and mucosal keratinocytes have been found to express PrPc. These data together with the recent finding that epithelial cells are able to support prion replication in vitro suggest that keratinocytes might play a role in the pathogenesis and/or transmission of prion diseases.