Glioblastoma multiforme is a fatal brain cancer which has eluded therapeutic advances. Although the genetic and epigenetic landscape of GBM is now well annotated, its pathogenesis remains elusive and difficult to study in the laboratory. By imitating two well documented alterations of GBM - p53 loss of function and activation of platelet derived growth factor receptor-alpha - we have created a new model of GBM and a tool to explore the kinetics of GBM initiation. In this model, cells from the subventricular zone of p53 null mice transform in vitro after approximately 100 days in PDGF-AA. Transformation is marked by abrupt, rapid proliferation, exogenous PDGF-AA independence, and the capacity to form invasive GBM-like tumors in p53 wild type, immunocompetent mice. This model offers the opportunity to study the nature and sequence of transformation-related events and potentially test novel therapeutics that target GBM in its earliest stages.