The dismal prognosis of glioblastoma had remained unchanged for the past 30 years until the association of temozolomide and radiotherapy in the breakthrough European Organization for Cancer/National Cancer Institute of Canada (EORTC/NCIC) trial brought new hope for patients. This trial will serve as a platform for new and exciting clinical and translational research areas. We review here the role of standard radiotherapy and chemotherapy in glioblastoma and the potential causes of their failure, and we focus on some of the aspects that led to the successful EORTC/NCIC trial and some of the related studies.