The FLI-1 gene and FLI-1 protein are best known for their critical role in the pathogenesis of ES/PNET. More than 85% of ES/PNET are characterized by the translocation t(11;22)(q24;q12) that results in the fusion of the ews gene on chromosome 22 to the FLI-1 gene on chromosome 11. FLI-1 is a member of the ETS (erythroblastosis virus-associated transforming sequences) family of DNA-binding transcription factors and is involved in cellular proliferation and tumorigenesis. FLI-1 is normally expressed in endothelial cells and in hematopoietic cells, including T lymphocytes. The immunohistochemical detection of FLI-1 protein has been shown in two recent studies to be valuable in the discrimination of ES/PNET from most of its potential mimics, with the notable exception of lymphoblastic lymphoma. The FLI-1 gene has also recently been shown to play an important role in the embryologic development of blood vessels. FLI-1 is a highly sensitive (92%) and specific (100%) marker of both benign and malignant vascular tumors. FLI-1 expression in the nonvascular sarcomas, melanomas, or carcinomas studied was not observed.