Many types of sarcomas are characterized by specific chromosomal translocations which are likely to be of etiologic significance. The recent elucidation of the molecular structure of the several of these translocations has revealed some striking similarities. Nearly all appear to result in the production of novel, tumor-specific chimeric transcription factors. Furthermore, six of the translocations, namely the t(11;22), t(21;22), and t(7;22) of Ewing's sarcoma, the t(12;22) of clear cell sarcoma, the t(12;16) of myxoid liposarcoma, and the t(11;22) of desmoplastic small round cell tumor, achieve this following a peculiar pattern, consisting in the fusion of a gene with an RNA-binding domain (EWS or TLS) with a transcription factor gene (FLI1, ERG, ETV1, ATF-1, CHOP, or WT1). The observation that the different translocation partners of the EWS gene are specifically associated with several distinct types of primitive sarcomas suggests a model in which the translocation partner supplying the DNA-binding domain confers the target specificity of the transcriptional activation mediated by these chimeric proteins, whereas the partner supplying the N-terminal domain and promoter region determines their transactivation potential and expression level. Further analysis of the normal functions and expression patterns of these genes should yield insights into the histogenesis of these different tumor types and into normal tissue development and differentiation. Clinically, our new understanding of the molecular structure of these translocations opens new avenues for molecular diagnosis and investigative therapeutics.