Glioblastoma multiforme is the most common primary brain tumor in adults. Despite major research efforts and progress in neuroimaging, neurosurgery, and radiation and medical oncology, the overall survival of patients with this disease has changed little over the past 30 years. Surgery and radiation therapy remain critical components in the care of patients with glioblastoma multiforme. Treatment with chemotherapy has been hampered by the apparent resistance of these tumor cells to available agents and challenges in delivering agents to the tumor cells. The blood-brain barrier can restrict entry of some agents and the effect of antiepileptic drugs inducing hepatic P450 can significantly affect the pharmacology of a wide range of antineoplastic agents. As a result, new agents and novel approaches are required. Translational research efforts should: (1) pursue a broad research agenda until productive avenues are identified; (2) quantify the delivery of novel agents to the malignant brain tumor cells; (3) determine the maximum tolerated dose (MTD) and preliminary efficacy data on novel agents before initiating combination therapies; (4) optimize trial designs; and (5) improve psychosocial and supportive care for patients with this devastating illness.