Fusion oncoproteins are a common cancer initiating event in pediatric malignancies, spanning the gamut of cancers observed in children from solid tumors to leukemias to brain tumors. Typically, they involve transcription factors or chromatin regulators and much less commonly kinases in pediatric cancers. Most often the fusion occurs in an otherwise simple genomic background with few other recurrent mutations. Ewing sarcoma is a canonical fusion driven pediatric cancer driven by the EWS-FLI1 fusion oncoprotein in the majority of cases. This presentation will focus on strategies to target Ewing sarcoma and other fusion oncoprotein-driven cancers including targeting the fusion directly as well as leveraging fusion biology toward novel therapies.