Ewing's sarcoma family of tumors (ESFT) affect patients between the ages of 3 and 40 years, with most cases occurring in the second decade of life. ESFTs are characterized by a translocation that occurs in 95% of tumors. This translocation joins the Ewing's sarcoma gene (EWS) located on chromosome 22 to an ets family gene; either friend leukemia insertion (FLI)1 located on chromosome 11, t(11;22), or ets-related gene (ERG) located on chromosome 21, t(21;22). The EWS-FLI1 fusion transcript encodes a 68 kDa protein with two primary domains. The EWS domain is a potent transcriptional activator, while the FLI1 domain contains a highly conserved ets DNA binding domain. ESFT presents a clinical challenge, especially in patients with metastatic disease in which dose-intensifying chemotherapy with bone-marrow transplantation does not improve survival. EWS-FLI1 is only present in ESFT cells and does not exist in any normal cell of the body. Experiments using ESFT cell lines or animal xenograft models have proven that EWS-FLI1 is required for tumor survival. Therefore, ESFT contains a unique protein generated by a tumor-specific translocation that has great potential as a molecular target for therapy. However, therapeutic applications directed towards eliminating or inactivating EWS-FLI1 have not reached the clinic. EWS-FLI1 has been a very difficult molecule to directly analyze in vitro due to poor solubility. Recent advances in generating recombinant EWS-FLI1 and novel data on the cellular functions of EWS-FLI1 should enhance progress towards understanding and application.