The current World Health Organization (WHO) classification system of primary brain tumors is solely based on morphologic criteria. However,there is accumulating evidence that tumors with similar histology have distinct molecular signatures that significantly impact treatment response and survival. Recent practice-changing clinical trials have defined a role for routine assessment of MGMT promoter methylation in glioblastoma patients,especially in the elderly,and 1p and 19q co-deletions in patients with anaplastic glial tumors. Recently discovered molecular alterations including mutations in IDH-1/2,EGFR,and BRAF also have the potential to become targets for future drug development. This article aims to summarize current knowledge on the molecular biology of high grade gliomas relevant to daily practice.