Malignant brain tumors strike deep into the psyche of those receiving and those delivering the diagnosis. Malignant gliomas, the most common subtype of primary brain tumors, are aggressive, highly invasive, and neurologically destructive tumors considered to be among the deadliest of human cancers. In its most aggressive manifestation, glioblastoma (GBM), median survival ranges from 9 to 12 months, despite maximum treatment efforts—a statistical fact that has changed little over several decades of technological advances in neurosurgery, radiation therapy, and clinical trials of conventional and novel therapeutics. Over the same time period, there has been an explosion of knowledge in cancer biology and basic science discovery that has fueled meaningful progress in the treatment of many common human cancers, including those of the breast, lung, and prostate. It is perplexing that therapies used effectively in the treatment of these solid tumors are overwhelmingly ineffective in the treatment of GBM, perhaps reflecting the eccentric biology and cellular origin of this neoplasm. To date, only one new agent has been documented to have modest activity against intermediate-grade gliomas, whereas no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is ironic that although a comprehensive view of the genetic lesions encountered in malignant gliomas has been compiled, substantive conceptual and practical barriers remain in assigning functional significance to these genetic changes and in harnessing this basic information into the development of drugs that make a difference in patient care. The history of treating malignant gliomas dates back to the middle of the 19th century and parallels landmark advances in modern surgical technique and the clinical discipline of neurology. The first brain tumor surgery of the modern era was performed in 1884 by Rickman

Godlee (Kaye and Laws 1995). By 1900, the initial enthusiasm for surgery had waned, because it became apparent that patients were not cured and that survival was only marginally prolonged. In efforts to improve surgical outcome, Harvey Cushing (1926), who had contributed major advances in surgical technique, pioneered the first histological grading scheme for gliomas and correlated it with clinical outcome (Kaye and Laws 1995). The grading scheme was based on the morphological resemblance of neoplastic cells to cell types found in the normal central nervous system (CNS). He and his colleague, Percival Bailey, described the seminal feature of gliomas, that is, their diffuse infiltrative nature, which renders them incurable by surgery alone. Radiation therapy was introduced soon thereafter in an attempt to cure these infiltrative tumors. Although clearly improving the median survival in intermediate-grade gliomas by many months and GBM by several months, the addition of radiation ultimately failed to alter long-term outcome (Bouchard and Pierce 1960). As chemotherapy was developed for leukemia and solid tumors, agents that could penetrate the blood–brain barrier were added to the treatment protocols of malignant gliomas. Nitrosurea-based chemotherapy, in combination with surgery and radiation therapy, emerged as the only regimen that improved median survival (Shapiro et al. 1989), predominantly in patients with intermediate-grade gliomas. Although nitrosureas have become standard therapy for malignant gliomas, it is now clear that patients are not cured with this or any other cytotoxic agent currently available, regardless of tumor grade.