Attempts to improve outcomes for patients with glioblastoma multiforme have focused largely on dose intensification and multimodal therapy and have been met with limited success. An alternative approach involves identifying and targeting the mechanisms responsible for tumour resistance. Recent data suggests that these high grade malignancies harbour a population of glioma stem cells that are both radioresistant and capable of initiating tumour regrowth. Furthermore, the radioresistant phenotype may be the consequence of constitutively upregulated and hyper-responsive cell cycle checkpoint pathways. This article considers whether these findings herald the dawn of a new era of effective, targeted therapy for this refractory tumour.