Patients with newly diagnosed glioblastoma multiforme should undergo a maximal tumor resection and then, whenever possible, should be entered into a clinical trial. The current standard of care consists of external beam irradiation, to a total of 60 Gy over 6 weeks, in combination with low-dose daily temozolomide, followed by at least six cycles of adjuvant temozolomide. If radiotherapy and a temozolomide-based adjuvant regimen fail, the most active treatment approach appears to be bevacizumab and irinotecan. Molecular therapy, with drugs targeting growth factor receptors and critical signal transduction pathway mediators, is also under active investigation.