Over the past few years, understanding the genetic abnormalities associated with glioblastoma, the most common malignant primary tumor of the central nervous system, has increased dramatically. Mutation types and frequencies have been comprehensively assessed, glioblastoma subclasses have been defined based on gene expression and methylation analyses, and novel mutations implicated in gliomagenesis have been identified. Nonetheless, a critical disconnect exists between achieved scientific advances and failure to improve patient outcome. Currently, standard therapy incorporating surgery, cranial irradiation, and temozolomide chemotherapy is uniformly applied for all patients. With this approach, median survival remains unacceptably poor including fewer than 10% of patients surviving 5 years after diagnosis. Salvage therapies are ineffective with PFS-6 rates under 10% for non-bevacizumab regimens and 40% for bevacizumab. Furthermore, all patients ultimately progress on bevacizumab, and then typically die from rapidly progressive tumor. Innovative treatment strategies directed to distinct patient subsets defined by specific genetic and gene expression analyses represent an attractive therapeutic paradigm shift for this highly challenging complex tumor, offering promise to ultimately improve outcome.