The prognosis of patients with glioblastoma (GBM) remains poor, and the use of hyperfractionation or dose escalation beyond 60 Gy has not conferred any survival benefit. More recently, hypofractionated radiotherapy (HFRT) has been employed as a novel approach for achieving dose escalation, with interesting results. We present here a systematic overview of the role and development of HFRT as a possible therapeutic strategy in patients with GBM. We searched the PubMed database for studies published since 1990 that reported on the tolerance, safety and survival outcomes after HFRT. These studies reported on the paradox of improved survival in patients developing central radionecrosis within the high-dose volume. Most series reported no significant increase in early or late toxicity, except for one study that reported visual loss in one patient at 7 months after treatment. More recently, studies of HFRT combined with concurrent temozolomide (TMZ) reported a trend towards improved survival compared with historical controls, with a few studies reporting a median survival of approximately 20 months. The interpretation of data from the above studies is limited by the heterogeneities of patient population and the significant variation in the range of employed dose schedules. However, high-dose HFRT using intensity-modulated radiotherapy appears to be a safe and feasible therapeutic option. There is a suggestion of improved outcomes on combining HFRT with TMZ, which warrants further investigation in a randomised trial.