The t(11;22)(q24;q12), present in 85% of Ewing's sarcoma and related tumours, fuses the EWS gene from chromosome 22q12 and the ETS family member, FLI–1. This results in the expression of a chimaeric protein containing the amino–terminal portion of EWS fused to the ETS DMA–binding domain of FLI–1. We have identified a second Ewing's sarcoma translocation, t(21;22)(q22;q12), that fuses EWS to a different ETS family member, the ERG gene located on band 21q22. Identical EWS nucleotide sequences found in the EWS/FLI–1 fusion transcripts are fused to portions of ERG encoding an ETS DNA–binding domain resulting in expression of a hybrid EWS/ERG protein. These findings suggest that fusion of EWS to different members of the ETS family of transcription factor genes may result in the expression of similar disease phenotypes.