The treatment of patients with intrinsic brain tumors is radically changing. This change is currently not (yet) signified by the use of targeted therapy in clinical practice but more by the definition of molecular markers as predictors for response to therapy which have been used for a long time. While in the past the choice of treatment has been based solely on the tumor entity and its degree of malignancy derived from histological analyses, large randomized trials have now provided a solid basis for personalized molecular-guided treatment decisions. For instance, in the German NOA-08 trial a benefit of chemotherapy with temozolomide alone was only demonstrated in a subgroup of elderly patients with malignant gliomas displaying promoter hypermethylation of the DNA repair enzyme MGMT. This is only one of several examples where molecular analysis of tumor tissue becomes clinically relevant as these analyses can and should be taken into account for treatment decisions and not, as previously, just as an additional parameter for estimating prognosis. This article illustrates the current developments in the area of personalized neurooncology and critically reviews the impact on clinical decision-making in daily practice.