The oral alkylating agent, temozolomide (Temodal: TMZ), is the only anticancer drug that has been shown in a phase III study to improve survival in glioblastoma (GBM) when administered with concomitant radiotherapy. Pharmacokinetic studies have documented relatively high concentrations of TMZ in brain tumors and cerebrospinal fluid (20-40% of the area under the plasma concentration curve), and other studies have demonstrated that TMZ is effective for treatment of various brain tumors, including recurrent and newly diagnosed glioma, primary CNS lymphoma, metastatic melanoma, and neuroblastoma. Molecular markers that predict a favorable response to TMZ plus concomitant radiotherapy include methylguanine methyltransferase (MGMT) promoter methylation patients with GBM and chromosome 1p/19q deletion in patients with anaplastic oligodendroglioma or low-grade glioma. Myelosuppression, nausea and constipation are relatively frequent in patients undergoing treatment with TMZ, and prophylaxis against Pneumocystis carinii pneumonia should be instituted. This article will summarize and discuss these issues as well as review ongoing and anticipated studies of TMZ in combination with other anti-cancer therapies.