Diffuse gliomas are a heterogeneous group of malignancies with highly variable outcomes, and diagnosis is largely based on histologic appearance. Tumor classification according to cell type and grade provides some prognostic information. However, significant clinical and biologic heterogeneity exists in glioma, even after accounting for known clinicopathologic variables. Significant advances in knowledge of the molecular genetics of brain tumors have occurred in the past decade, largely because of the availability of high-throughput profiling techniques, including new sequencing methodologies and multidimensional profiling by The Cancer Genome Atlas project. The large amount of data generated from these efforts has enabled the identification of prognostic and predictive factors and helped to identify pathways driving tumor growth. Implementing these signatures into the clinic to personalize therapy presents a new challenge. Identification of relevant biomarkers, especially when coupled with clinical trials of newer targeted therapies, will enable better patient stratification and individualization of treatment for patients with glioma.