CIC encodes a transcriptional repressor with a high-mobility group (HMG)-box containing DNA-binding domain that functions as a primary downstream sensor of receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway activity. CIC-DUX4 sarcoma (CDS) is a recently characterized subset of high-grade sarcoma that accounts for the majority of Ewing-like small round cell sarcomas. CIC-DUX4 gene fusion, which fuses capicua (CIC) to the double homeobox 4 gene (DUX4), resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Despite histological similarities to Ewing sarcoma, CIC-DUX4–positive sarcomas are clinically distinct and typically characterized by the rapid development of lethal metastatic disease and chemoresistance. The molecular targets regulated by the CIC-DUX4 oncoprotein that promote this aggressive malignancy remain largely unknown.