Neural stem cells (NSCs) are thought to be the cell of origin in glioblastoma multiforme (GBM), an aggressive brain tumor in humans. Now, Inder Verma and colleagues suggest that dedifferentiation of neurons and astrocytes into an NSC or progenitor state can induce gliomas in a mouse model (Science, published online 18 October 2012; doi:10.1126/science.1226929). The authors established a mouse glioma model with Cre-inducible lentiviral vectors expressing short hairpin RNAs (shRNAs) for Nf1 and Tp53, as it has been shown previously that loss of these factors leads to the formation of high-grade gliomas. Injection of the vectors into Synapsin I–Cre mice, in which they should target neurons but not glial cells, resulted in glioma formation. The authors then targeted more mature neurons by injecting CamK2a-Cre mice with the Cre-inducible lentiviral vectors, which led to the development of tumors but with a much longer latency, suggesting that mature neurons may be more refractory to transformation. The authors found that, as the tumors progressed, expression of progenitor/stem cell markers increased, while expression of differentiated state markers decreased. The authors then transformed primary cortical astrocytes in vitro and transplanted them into immunodeficient mice. The resulting tumors also expressed progenitor markers, showing that terminally differentiated astrocytes undergo dedifferentiation during tumorigenesis.