Despite surgery, radiation and chemotherapy, the prognosis for high-grade glioma (HGG) is poor. Our understanding of the molecular pathways involved in gliomagenesis and progression has increased in recent years, leading to the development of novel agents that specifically target these pathways. Results from most single-agent trials have been modest at best, however. Despite the initial success of antiangiogenesis agents in HGG, the clinical benefit is short-lived and most patients eventually progress. Several novel agents, multi-targeted agents and combination therapies are now in clinical trials for HGG and several more strategies are being pursued.