Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, treatment for most primary brain tumors remains inadequate. Most are associated with a high rate of recurrence after primary therapy and a dismal outcome following recurrence. Surgery and radiation remain the primary modalities of therapy for malignant brain tumors. The role of chemotherapy in malignant gliomas, especially glioblastoma multiforme, has been inconclusive. However, a recent trial by the European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada combining radiation therapy with temozolomide for newly diagnosed glioblastoma patients showed a significantly improved survival benefit over radiation therapy alone. In addition to this encouraging progress, recent experience has shown that selected malignant brain tumors--for example, anaplastic oligodendrogliomas, primary central nervous system lymphomas, medulloblastomas, and intracranial germ cell tumors--are often highly responsive to chemotherapy. Molecular genetic studies are becoming indispensable aids in the diagnosis and treatment of the malignant gliomas. For example, we have learned that allelic loss of chromosome 1p is a significant predictor of chemosensitivity, whereas combined loss of chromosomes 1p and 19q is a strong predictor of chemosensitivity, progression-free survival, and overall survival in patients with anaplastic oligodendroglioma. Similarly, MGMT promoter methylation is associated with more frequent responses and longer survival in patients with glioblastoma multiforme receiving temozolomide-based therapy. These and other recent advances have led to the development and testing of several novel chemotherapeutic and molecular-targeted agents. Several different approaches and modalities to improve the efficacy of chemotherapy (eg, MGMT promoter methylation) are currently under way. Clinical trials implementing angiogenesis inhibitors, biologic modifiers, or molecular-targeted therapies are also actively being investigated.