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Glioblastoma, the most aggressive cerebral tumor, is invariably lethal. Glioblastoma cells express several genes typical of normal neural stem cells. One of them,  SOX2 , is a master gene involved in sustaining self‐renewal of several stem cells, in particular neural stem cells. To investigate its role in the aberrant growth of glioblastoma, we silenced  SOX2  in freshly derived glioblastoma tumor‐initiating cells (TICs). Our results indicate that  SOX2  silenced glioblastoma TICs, despite the many mutations they have accumulated, stop proliferating and lose tumorigenicity in immunodeficient mice. SOX2 is then also fundamental for maintenance of the self‐renewal capacity of neural stem cells when they have acquired cancer properties. SOX2, or its immediate downstream effectors, would then be an ideal target for glioblastoma therapy. S TEM  C ELLS   2009;27:40–48

SOX2 Silencing in Glioblastoma Tumor‐Initiating Cells Causes Stop of Proliferation and Loss of Tumorigenicity