Cancer cells are driven by both genetic and epigenetic changes, but their relative contribution in driving the malignant phenotype remains unclear. We have used induced pluripotent stem (iPS) methodology to demonstrate that highly malignant and aneuploid human glioblastoma cells can be epigenetically reprogrammed. Glioblastoma-iPS cells (GiPSCs) activate expression of early embryonic markers such as NANOG, and display widespread reconfiguration of DNA methylation patterns including reactivation of aberrantly silenced tumour suppressor. Removal of epigenetic restrictions enables these GiPSCs to enter alternative differentiation programs in vitro and in vivo.