The Ewing sarcoma family of tumors (ESFT) consists of a group of tumors characterized by morphologically similar round-cell neoplasm and by the presence of a common chromosomal translocation. Although rare, such tumors constitute the third most frequent primary sarcoma of bone after osteosarcoma and chondrosarcoma. ESFT most commonly affects young children and adolescents. Because most patients with clinically apparent localized disease at diagnosis may also have occult metastatic (ie, systemic) disease, multidrug chemotherapy as well as local disease control with surgery and/or radiation therapy are indicated for all patients. Despite marked improvements in survival during the past 40 years for patients with localized disease, lesser improvements have been seen in patients with metastatic or recurrent disease. A better understanding of the complex biology of ESFT may lead to the successful development of biologically targeted therapies. As the regulatory pathways responsible for transformation, growth, and metastasis of ESFT become more refined, the number of potential therapeutic targets will expand.