Recent therapeutic advances have improved standard treatment for patients with newly diagnosed glioblastoma. Unfortunately, even with these improvements, only a fraction of patients derive significant benefit and experience prolonged survival. These findings are consistent with long-standing clinical and recent molecular evidence that subtypes of glioblastoma exist with differing survival rates and response to treatment. However, patients with newly diagnosed glioblastoma are currently treated in a uniform fashion, without regard for potential underlying differences in molecular alterations or prognosis. In this review, we will discuss recent progress toward the identification of robust and clinically relevant molecular subgroups of glioblastoma and initial steps in using this information to individualize therapy and overcome treatment resistance.