The CIC gene encodes a transcriptional repressor that inhibits the expression of the PEA3 (polyoma enhancer activator 3) gene family, including ETV1, ETV4, and ETV5 and regulates receptor tyrosine kinase signaling pathways. Rearrangements involving the CIC gene are frequently found in EWSR1-negative small blue round cell tumors (SBRCT) which arise in soft tissues of children and young adults and have been described as aggressive tumors with an inferior overall survival compared to Ewing sarcoma (EWS). The CIC-DUX4 (double homeobox 4) gene fusion is the most frequent genetic event in EWSR1-negative SBRCT resulting from either a t(4;19)(q35;q13.2) or a t(10;19) (q26.3;q13.2). CIC rearrangements have also been found in other tumor entities such as lung cancer and medulloblastomas and other fusion partners besides DUX4 are known (FOXO4, LEUTX). As CIC-DUX4-positive patients do not respond well to the common forms of EWS treatment, and show a poor overall survival, novel therapy approaches are needed to treat this type of aggressive tumors. Hence, the detection of CIC translocations by Fluorescence in situ Hybridization (FISH) may be of prognostic and therapeutic relevance.