The epithelial-to-mesenchymal transition has been described in a number of epithelial tumors as a process in which tumor cells lose epithelial characteristics and normal cell-cell interactions and acquire a mesenchymal and more invasive phenotype.23 The molecular mechanisms that regulate epithelial-to-mesenchymal transition in cancer are complex and often show tissue specificity. Pathways that have been described to promote epithelial-to-mesenchymal transition include transforming growth factor β, Wnt, PI3-K/AKT, EGFR, and Ras.24- 29 While a mesenchymal transition has not been formally described in the literature as a general property of gliomas, the unusual but well-documented entity of gliosarcoma suggests that it indeed occurs. While the original description of gliosarcoma postulated that the glial and mesenchymal components arise from different cell types, more recent evidence indicates a single cell of origin,30 suggesting that the mesenchymal component results from transdifferentiation of the glial component. Examination of microarray data obtained by us9,11 as well as others22 indicates that high expression of mesenchymal and angiogenic genes is common in glioblastoma and associated with worse outcomes.11,22 Furthermore, these findings suggest that the histopathologic entity of gliosarcoma may simply represent the extreme example of this phenomenon. Given these observations, the availability of agents that target the PI3-K/AKT, Ras/Raf, and transforming growth factor β pathways or other pathways associated with epithelial-to-mesenchymal transition, alone or combined with agents that target angiogenesis, may represent a rational approach for tumor-specific therapy of glioblastomas, demonstrating this molecular signature.