High-grade gliomas (HGGs) should be treated with maximal, safe surgical resection followed by 57-60 Gy of partial-field external beam or intensity-modulated radiotherapy to a 2 cm margin surrounding the resection cavity. The standard of care for newly diagnosed glioblastoma includes concurrent temozolomide (TMZ) during radiotherapy and adjuvant TMZ for six or more cycles. The optimal role of chemotherapy in anaplastic gliomas is unresolved. Carefully selected patients with anaplastic gliomas can be treated with combination chemotherapy (procarbazine, lomustine, vincristine; PCV) or TMZ as initial therapy after surgical resection, adjuvant therapy after radiotherapy, or at recurrence in patients with anaplastic glioma. Patients with recurrent glioblastoma can be treated with intravenous bevacizumab or dose-intense regimens of TMZ, but selection of optimal candidates for either therapy is unresolved. Other currently available targeted biologic agents are not part of routine management of patients with HGGs. Combination therapeutic trials of antiangiogenic and other targeted agents are ongoing in patients with HGGs. The way forward for patients with HGGs will involve treatments targeting the molecular abnormalities that are important to tumor initiation and growth. All patients with HGGs should be evaluated for clinical trial eligibility at diagnosis and upon recurrence.