Recent advances in molecular analysis and genome sequencing have prompted a paradigm shift in neuropathology. This article discusses the discovery and clinical relevance of molecular biomarkers in diffuse gliomas in adults and how these biomarkers led to revision of the World Health Organization classification of these tumors. We relate progress in clinical classification to an overview of studies using molecular profiling to study gene expression and DNA methylation to categorize diffuse gliomas in adults and issues dealing with intratumoral heterogeneity. These efforts will refine the taxonomy of diffuse gliomas, facilitate selection of appropriate treatment regimens, and ultimately improve patient’s lives.