Malignant gliomas are the most common primary brain tumors and have devastatingly high mortality rates. Most recurrences are close to the surgical bed, despite adjuvant fractionated radiotherapy (FRT). Localized FRT to total dose of 60 Gy with concurrent and adjuvant temozolomide (TMZ) resulted in a statistically significant survival improvement of patients with newly diagnosed glioblastoma compared to those treated with FRT alone, and has emerged as the cornerstone of therapy. Despite this progress, long-term survival remains poor. Various signaling pathways have become the targets of different biological agents. Disruption of the vascular endothelial growth factor (VEGF) signaling is particularly attractive, but overall survival remained unchanged despite administration of bevacizumab. Cediranib and mammalian target of rapamycin (mTOR) inhibitors, which also alter VEGF signaling, are currently under investigation. Studies on epidermal growth factor receptor (EGFR) and integrin inhibitors (e.g., cilengitide) have had disappointing results. There is active investigation into other agents that will hopefully enhance the cytotoxic effects of FRT and TMZ.