Malignant gliomas remain among the most treatment-refractory tumors. Traditional upfront treatment regimens have incorporated nitrosurea-based chemotherapy. This strategy has evolved to include temozolomide-based approaches. Promising Phase I/II data with TMZ in the recurrent setting prompted a Phase III EORTC study of TMZ in combination with RT for patients with newly diagnosed GBM. The landmark EORTC 26981-22981/NCIC CE3 study demonstrated a significant improvement in not only median survival, but also in terms of 2-year survival. Given that over one-quarter of the patients enrolled on the TMZ + RT arm survived beyond 2-years, there appears to be a finite percentage of patients who derive long-term benefit from this treatment regimen. Given that the EORTC-based regimen represents an incremental improvement in the standard of care, rather than a truly curative solution for most patients, further efforts must be expended to identify novel therapeutic approaches. To this end, targeted therapies have emerged as an attractive option. Accumulating evidence suggests that certain molecular pathways are selectively upregulated in tumor vs. normal cells. Some of these pathways have been shown to be instrumental in proliferation, migration, invasion, angiogenesis, and/or survival in preclinical models. These would appear to represent ideal therapeutic targets, as their antagonism may lead to an improvement in the therapeutic ratio of radiation. Emerging data from clinical studies on "first generation" targeted therapies appear to demonstrate benefit for select patients. Further molecular/genetic profiling must be undertaken to identify exactly which patients benefit.