The Ewing sarcoma breakpoint region 1 (EWSR1; also known as EWS) represents one of the most commonly involved genes in sarcoma translocations. In fact, it is involved in a broad variety of mesenchymal lesions which includes Ewing's sarcoma/peripheral neuroectodermal tumor, desmoplastic small round cell tumor,clear cell sarcoma, angiomatoid fibrous histiocytoma, extraskeletal myxoid chondrosarcoma, and a subset of myxoid liposarcoma. The fusion products between EWSR1 and partners usually results in fusion of the N-terminal transcription-activating domain of EWSR1 and the C-terminal DNA-binding domain of the fusion partner, eventually generating novel transcription factors. EWSR1 rearrangement can be visualized by the means of fluorescence in situ hybridization (FISH). As soft tissue sarcomas represent a diagnostically challenging group, FISH analysis is an extremely useful confirmatory diagnostic tool. However, as in most instances a split-apart approach is used, the results of molecular genetics must be evaluated in context with morphology.