Despite decades of intense research, the complex biology of glioblastoma (GBM) is not completely understood. Progression-free survival and overall survival have remained unchanged since the implementation of the STUPP regimen in 2005 with concomitant radio-/chemotherapy and adjuvant chemotherapy with temozolomide. In the context of Hanahan and Weinberg’s six hallmarks and two emerging hallmarks of cancer, we discuss up-to-date status and recent research in the biology of GBM. We discuss the clinical impact of the research results with the most promising being in the hallmarks ‘enabling replicative immortality’, ‘inducing angiogenesis’, ‘reprogramming cellular energetics’ and ‘evading immune destruction’. This includes the importance of molecular diagnostics according to the new WHO classification and how next generation sequencing is being implemented in the clinical daily life. Molecular results linked together with clinical outcome have revealed the importance of the prognostic biomarker isocitratedehydrogenase (IDH), which is now part of the diagnostic criteria in brain tumours. IDH is discussed in the context of the hallmark ‘reprogramming cellular energetics’. O-6-methylguanine-DNA methyltransferase status predicts a more favourable response to treatment and is thus a predictive marker. Based on genomic aberrations, Verhaak et al have suggested a division of GBM into three subgroups, namely, proneural, classical and mesenchymal, which could be meaningful in the clinic and could help guide and differentiate treatment decisions according to the specific subgroup. The information achieved will develop and improve precision medicine in the future.