We show the let-7 family member let-7a to be a direct EWS-FLI-1 target gene, whose in vivo repression promotes ESFT cell tumorigenicity via induction of its target gene HMGA2. More importantly, we demonstrate that systemic delivery of synthetic let-7a significantly decreases tumor growth in vivo, providing a potentially potent novel therapeutic option in ESFT. The gene discussed is HMGA2; the disease is neoplasm.