Ewing's sarcoma is a solid tumor of the bone that primarily occurs in children and young adults. Most cases harbor the (11;22) (q24;q12) chromosomal translocation that encodes the EWS/FLI oncoprotein. EWS/FLI is an aberrant ETS-type transcription factor that dysregulates a number of genes important in the development of Ewing's sarcoma. Because EWS/FLI is the key oncoprotein in this tumor and ETS proteins are often dysregulated in various human cancers, Ewing's sarcoma serves as a useful paradigm for ETS-mediated oncogenesis. We recently showed that EWS/FLI interacts with GGAA-microsatellites to regulate some of its target genes, including NR0B1, an EWS/FLI-regulated gene that is required for the oncogenic phenotype of Ewing's sarcoma. While microsatellites typically have no ascribed function, and are sometimes considered "junk" DNA, our findings provide a unique role for microsatellites in cancer development. Furthermore, these findings may indicate a novel mechanism for normal ETS protein function as well. Finally, it is tempting to speculate that microsatellite polymorphisms may confer differences in susceptibility to Ewing's sarcoma, both between individuals and between populations, and other diseases mediated by ETS transcription factors. The observation of microsatellites as transcriptional response elements for EWS/FLI suggest that these elements may not be "junk" after all.