Thyroid transcription factor-1 (TTF-1) is a 38-kd homeodomain containing DNA-binding protein originally identified in follicular cells of the thyroid and subsequently in pneumocytes. This review focuses on the utility of antisera in TTF-1 immunohistochemical staining in the diagnosis of neoplastic conditions. Based on published studies to date, anti-TTF-1 is a very useful reagent in distinguishing pulmonary adenocarcinoma from other primary carcinomas, identifying differentiated thyroid neoplasms, distinguishing mesothelioma from pulmonary adenocarcinoma, and distinguishing small cell carcinoma of the lung from Merkel cell carcinoma. It may also be useful in distinguishing neuroendocrine (NE) tumors of the lung from well-differentiated NE tumors from other sites, such as the intestine.