Friend leukemia integration-1 (Fli1) is a member of the Ets (E26 transformation-specific) transcription factor family, which was initially identified as a proto-oncogene in Friend virus-induced erythroleukemia in mice. In humans, Fli1 gene is rearranged in 90% of Ewing sarcoma family of tumors, which includes morphological variants of Ewing sarcoma and peripheral primitive neuroectodermal tumor. Under physiological conditions, Fli1 is expressed at high levels in both hematopoietic and endothelial cells. Fli1 is also expressed in dermal fibroblasts even though the levels are relatively lower compared with those cells. Consistently, Fli1 plays a pivotal role in megakaryocytic differentiation and myelomonocytic, erythroid, and natural killer (NK) cell development, in vascular development and angiogenesis, and in the process of extracellular matrix remodeling. Altered expression of Fli1 in these cell types may be associated with the developmental process of systemic lupus erythematosus and systemic sclerosis.