EWS/FLI is the defining mutation of Ewing sarcoma. This oncogene drives malignant transformation and progression and occurs in a genetic background characterized by few other recurrent cooperating mutations. In addition, the tumor is absolutely dependent on the continued expression of EWS/FLI to maintain the malignant phenotype. However, EWS/FLI is a transcription factor and therefore a challenging drug target. The difficulty of directly targeting EWS/FLI stems from unique features of this fusion protein as well as the network of interacting proteins required to execute the transcriptional program. This network includes interacting proteins as well as upstream and downstream effectors that together reprogram the epigenome and transcriptome. While the vast number of proteins involved in this process challenge the development of a highly specific inhibitors, they also yield numerous therapeutic opportunities. In this report, we will review how this vast EWS-FLI transcriptional network has been exploited over the last two decades to identify compounds that directly target EWS/FLI and/or associated vulnerabilities.