High grade gliomas (HGG) are the most common brain tumor in adults, with 15,000 new cases/year in the USA. Despite progress made using combination therapies including surgery, radiation and/or chemotherapy, the treatment of HGG remains challenging with a typical median survival of 6-12 months for patients with newly diagnosed glioblastoma multiforme (GB) and 24-36 months for patients with anaplastic astrocytoma. The time to tumor progression of patients with recurrent GBM is nine weeks and the median survival is 25 weeks, while for recurrent anaplastic astrocytomas (AA), the time to tumor progression is 13 weeks and the median survival is 47 weeks. More recently, single-agent Avastin has been seen to improve 6-month progression-free survival (PFS-6) to 42.6% as well as increase Median Overall Survival to 9.3 months in patients with recurrent GBM. However, chemotherapy treatment for malignant gliomas has limitations given the low activity of available antineoplastic agents, the emergence or de-novo presence of resistance to such agents, the sensitivity of the brain to irreversible damage from a therapeutic modality, and the compromised delivery of these agents to partially privileged intracranial sites. Effective agents with novel mechanisms of action need to be evaluated in HGG which account for these limitations.