Twenty undifferentiated skin tumors were examined by immunostaining in an attempt to achieve more precise identification. Light microscopy yielded only a differential diagnosis, whereas immunostaining of formalin-fixed, paraffin-embedded tissue sections with a panel of antibodies to intermediate filaments and other cell components led to a definitive diagnosis. Four cytokeratin-positive epithelial tumors were subtyped into squamous cell carcinomas and adenocarcinomas with the use of antibodies to different cytokeratin polypeptides. Fifteen vimentin-positive tumors were subdivided into malignant melanomas with the use of antibody to S-100 protein, lymphomas with the use of antibody to immunoglobulin, and mesenchymal tumors (angiosarcomas, atypical fibroxanthomas, dermatofibrosarcoma protuberans, and meningiomas) with the use of antibody to S-100 protein, factor VIII, and lysozyme. One desmin-positive tumor was diagnosed as a leiomyosarcoma of the skin. A scheme is presented for using immunohistochemistry to facilitate the diagnosis of undifferentiated tumors involving the skin.