Diffuse gliomas are the most common primary brain tumors, with glioblastoma (GBM) encompassing more than 50 % of all cases. Despite aggressive therapy, patients nearly always succumb to their disease and the survival for patients with GBM is approximately 1 year. During past years, numerous scientific contributions have reshaped the field of neuro-oncology and neuropathology. A series of molecular discoveries have shed light on new pathogenic mechanisms, as well as new prognostic and predictive biomarkers with clinical relevance. The current World Health Organization (WHO) classification system is solely based on morphologic criteria; however, there is accumulated evidence that tumors with similar histology have distinct molecular signatures with a clinically significant impact on treatment response and survival. Molecular markers and signatures could be incorporated into the glioma classification and grading system to mirror the clinical outcomes. Additionally, molecular markers could lead to a redefinition of currently controversial entities, such as mixed oligoastrocytomas. Newly discovered molecular alterations also have the potential to become targets for future drug development. Despite tremendous progress in the past decade, therapeutic progress for diffuse gliomas has been slow. A further understanding of glioma biology, in concert with well-designed clinical trials, is necessary to identify more putative molecular biomarkers and unravel the mysteries in the pathogenic mechanisms that trigger this menacing disease.