Malignant gliomas are one of the most difficult tumors to treat, with only modest advances being made in the past few decades. Surgery and radiation have had the greatest impact, increasing survival. Chemotherapy modestly increases survival. The use of chemotherapy in the treatment of malignant gliomas is the focus of this paper and the more commonly used agents at diagnosis and relapse are reviewed. Since most patients fail first-, second- and even third-line agents that are commercially available, some of the more relevant new biological compounds will also be discussed. As treatments for brain tumors evolve, it is likely that optimal therapies will come from combination therapies that incorporate target-specific and chemotherapeutic agents.