Background: Patients with newly diagnosed glioblastoma without O6-methyl guanine O6-methylatransferase (MGMT) promoter methylation do not benefit from alkylating therapy. Clinical trials aiming at replacing temozolomide (TMZ) with targeted agents in unselected patient populations have failed to demonstrate any benefit. Advances in the understanding of glioblastoma at a molecular level along with technological progress have led to the identification of key genetic alterations in a timely manner allowing for treatment decisions in newly diagnosed patients. In this setting, these alterations not only refine the sub-classification of glioblastoma, but also allow for subset specific treatments, with contemporary analyses allowing for differentiating prognostic and predictive biomarkers. Methods: N²M² is an open label phase I/II umbrella trial for patients with newly diagnosed glioblastoma without MGMT promoter methylation to show safety, feasibility and preliminary efficacy (decision for future randomized phase II/III) of treatment with targeted compounds in addition to radiotherapy based on thorough molecular characterization. N²M² is formally divided into a DISCOVERY and a TREATMENT aspect. DISCOVERY includes the use of panel, whole exome and transcriptome sequencing, methylome analysis using Illumina EPIC arrays, and gene expression arrays to find new, unexpected targets and get a comprehensive view on affected pathways, with dedicated bioinformatics evaluation (GUIDE), a Molecular Tumor Board and a timely initiation (≤ 4 weeks) of the postoperative treatment. Stratification for TREATMENT takes place in seven subtrials according to the best matching molecular alteration. For the phase I parts, a maximum of 9 patients will be enrolled in each cohort. A Bayesian criterion is used for continuous monitoring of toxicity. In the phase II trials, progression-free survival at six months is used as endpoint for efficacy. Patients with no matching alteration receive the standard chemoradiotherapy with TMZ and serve as contemporary, non-randomized controls with an estimated PFS6 of 40%.