Ewing sarcoma is one of the most common and lethal pediatric cancers. Five-year survival for those with metastatic disease is less than 30%. In contrast to major advances in most of the other pediatric cancers, a fivedrug cytotoxic regimen has been the mainstay for its treatment for the past three decades. Also used to treat these sarcomas are surgery and radiation therapy, which may be disfiguring or carry significant morbidity. Current therapies may also contribute to the increased incidence of second malignancies in survivors of Ewing sarcoma. Thus, there is a great need for more effective, less toxic therapies. One major obstacle to progress is the paucity of animal models. Our goal is to develop zebrafish models for Ewing sarcoma that will provide new insights into the pathogenesis and develop new therapies that will improve survival. Fish have multiple advantages to mice: 1) The fish develop within several days and are transparent; 2) Cancers develop faster in fish than mice; 3) Fish can be genetically manipulated more easily and quickly; 4) Drugs can be more easily administered; and 6) The costs are significantly less. Here, we will use our newly created zebrafish transgenic lines and mutants to study the pathophysiology and metastasis of Ewing sarcoma. These novel studies are feasible within one year of VeloSano funding. Our development of unique animal models which harbor the genetic lesions that are found in children and adolescents with Ewing sarcoma will be critical for development and validation of new agents to treat this cancer more effectively and with less toxicity.