For more than three decades, alkylating agents have been the most widely used class of chemotherapeutic agents for the treatment of glial brain tumors. Today, concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma. Temozolomide alone or in combination with radiotherapy is being explored in ongoing trials in newly diagnosed patients with low-grade and anaplastic glioma. Rechallenge with alternative dosing schedules of temozolomide is a valid treatment option in recurrent, temozolomide-pretreated patients with glioblastoma, and nitrosourea compounds are alternative treatment options in this setting, in addition to novel, mostly antiangiogenic agents, notably bevacizumab. Moreover, nitrosoureas have become the gold standard comparator arm for the evaluation of novel treatments in recurrent glioblastoma.