Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, characterized by high degrees of inter-tumor and intra-tumor heterogeneity. Despite significant advancements in understanding its molecular pathogenesis and biology, the prognosis for GBM patients remains poor. This review systematically discusses key achievements in the understanding of GBM molecular pathogenesis, mechanisms, and biomarkers over the past decade. It covers advances in molecular pathology, including genetics, epigenetics, transcriptomics, and signaling pathways, as well as the development of molecular biomarkers with potential clinical roles. The review also highlights new strategies, current challenges, and future directions for discovering new biomarkers and therapeutic targets for GBM. Key molecular alterations in GBM include TERT promoter mutations, PTEN deletion, EGFR amplification, ATRX mutation, and TP53 mutation. Epigenetic changes, such as DNA methylation, have also been extensively studied and shown to be potential biomarkers and drug targets. Transcriptomic studies have identified distinct subtypes of GBM, which have prognostic and therapeutic implications. The review emphasizes the importance of integrating genetic, epigenetic, and transcriptomic data to refine GBM classification and improve patient management. Finally, it discusses the challenges and future directions in the implementation of molecular discoveries into clinical practice, including the need for combination therapy and addressing intratumor heterogeneity.Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, characterized by high degrees of inter-tumor and intra-tumor heterogeneity. Despite significant advancements in understanding its molecular pathogenesis and biology, the prognosis for GBM patients remains poor. This review systematically discusses key achievements in the understanding of GBM molecular pathogenesis, mechanisms, and biomarkers over the past decade. It covers advances in molecular pathology, including genetics, epigenetics, transcriptomics, and signaling pathways, as well as the development of molecular biomarkers with potential clinical roles. The review also highlights new strategies, current challenges, and future directions for discovering new biomarkers and therapeutic targets for GBM. Key molecular alterations in GBM include TERT promoter mutations, PTEN deletion, EGFR amplification, ATRX mutation, and TP53 mutation. Epigenetic changes, such as DNA methylation, have also been extensively studied and shown to be potential biomarkers and drug targets. Transcriptomic studies have identified distinct subtypes of GBM, which have prognostic and therapeutic implications. The review emphasizes the importance of integrating genetic, epigenetic, and transcriptomic data to refine GBM classification and improve patient management. Finally, it discusses the challenges and future directions in the implementation of molecular discoveries into clinical practice, including the need for combination therapy and addressing intratumor heterogeneity.