Malignant gliomas are the most common primary central nervous system tumors, and the most aggressive and frequent form is the World Health Organization (WHO) grade IV astrocytoma, or glioblastoma. The standard treatment of glioblastoma consists of aggressive resection, radiation therapy, and concomitant and adjuvant treatment with the DNA-alkylating agent temozolomide. Despite treatment, the prognosis is dismal for the vast majority of glioblastoma patients, with over 90% of patients succumbing to the disease within 5 years and a median survival of just over 1 year after diagnosis. There is clearly a great need for the development of therapeutic agents targeting pathways driving glioma malignancy, including cell proliferation, invasion, survival, as well as angiogenesis and pathways leading to resistance to cytotoxic therapies. Identification and validation of biomarkers predictive of response to therapy for patient stratification is an essential component of the development of targeted therapies. Comprehensive molecular characterization of tumor tissues is becoming prevalent, and developing approaches to integrate and bring this knowledge to the clinic will fuel the incorporation of targeted therapy in the management of malignant gliomas.