Ewing sarcoma (ES) is a highly aggressive bone and soft-tissue tumor with peak incidence among adolescents and young adults. Despite advances in local control and systemic chemotherapy, metastatic relapse after an initial clinical remission remains a significant clinical problem. In addition, metastasis at the time of presentation or at relapse continues to be the leading cause of death for patients diagnosed with ES. Since the discovery of the pathognomonic EWS− FLI1 fusion gene more than 20 years ago, much about the molecular and cellular biology of ES pathogenesis has been learned. In addition, more recent exploitation of advances in stem cell and developmental biology has provided key insights into the cellular origins of ES and the role of epigenetic deregulation in tumor initiation and maintenance. Nevertheless, the mechanisms that drive tumor relapse and metastasis remain largely unknown. These gaps in our knowledge continue to hamper the development of novel therapeutic strategies that may improve outcomes for patients with relapsed and metastatic disease. In this article we review the current status of ES biology research, highlighting areas of investigation that we consider to have the greatest potential to yield findings that will translate into clinically significant advances.