Ewing’s sarcoma is characterized by the presence of fusion oncoproteins involving EWSR1 and an ETS gene, most commonly FLI1. In this issue of Cancer Cell, Smith et al. have combined RNA interference with expression profiling to study the pattern of gene expression downstream of the most common of these fusions, EWS/FLI. Using this strategy, Smith et al. have identified a homeobox gene, NKX2.2, which is both highly expressed in Ewing’s sarcoma and essential for the transforming activity of EWS/FLI.