The histogenesis of mammary and extramammary Paget's disease has been studied by immunohistochemical staining of paraffin-embedded tissue using a panel of epithelial cell markers, which react with secretory or ductal epithelium, but not stratified epithelium. These markers included a monoclonal antibody E29 to epithelial membrane antigen EMA, the cytokeratin marker CAM 5.2 and three new monoclonal antibodies raised to human milk fat globule membrane (LICR-LON-TW19 and H.10.A) and a human bladder cell cancer line (3.77). The findings demonstrate that both mammary and extramammary Paget's disease are of epithelial cell origin and share antigens expressed by simple epithelia. Some antigens, such as EMA and low molecular weight cytokeratins are consistently present in both diseases, whereas other antigens, identified by H.10.A and TW19 are found more frequently in cases of extramammary Paget's disease. This panel of monoclonal antibodies also proved useful in distinguishing Paget's disease from pagetoid melanoma and clear cell Bowen's disease.