Glioblastoma is the most frequent primary brain tumor in adults. The average survival time of less than 1 year did not improve notably over the last three decades. The dismal prognosis of glioblastoma patients is largely due to the striking radioresistance of this tumor. Here, we attempt a combined view on the genetics, the repair mechanisms and the radioresistance of glioblastoma. Specifically, we address the role of DNA-PKcs and the novel potential end-joining factor KUB3 in maintaining the radioresistant phenotype, the interrelationship between genetic lesions and repair mechanisms, and new perspectives that emerge from the identification of glioblastoma stem cells.