Ewing's sarcoma (ES) and related neoplasias are characterized by the reciprocal translocation, t(11;22)(q24;q12). The translocation has been reported to generate a fusion gene between the EWS (a previously undescribed gene on chromosome 22) and FLI1 genes. We report a similar translocation of EWS and FLI1 in an Askin's tumor cell line (SK-NM-C). Further, we describe an alternative translocation in an ES cell line (#5838) in which the 5' end of the EWS gene is juxtaposed to the 3' end of the ERG gene. The ERG gene is on chromosome 21, but no microscopically visible changes in chromosome 21 were observed. Elevated steady state levels of the EWS/ERG fusion gene transcript were detected in the #5838 cell line. This is the first report of a structural alteration of ERG in human cancer. Also, it confirms a general mechanism of generating putative oncogenic fusion genes by placing an ETS DNA binding domain in direct proximity to the carboxy terminus domain (CTD) related region of the EWS gene.