Abstract Brain cancer is now the deadliest form of childhood cancer in the United States. In particular, Group3 Medulloblastoma (MB) is the pediatric brain tumor with the highest morbidity and mortality. Patients with Group3 MB currently have the worst outcome and nearly 50% are metastatic at the time of diagnosis. However, the cellular and molecular mechanisms underlying Group3 MB are still unknown. What is still lacking in the field is the possibility to obtain tumors by direct genetic modification of mice and to be able to recapitulate the growth and metastasis formation of Group3 MB. Exploiting in-vivo transfection of mouse cerebellar cells with CRISPR-Cas9 and PiggyBac transposase systems, we tested different combinations of putative oncosuppressors and putative oncogenes, derived from human Medulloblastoma NGS data, for their ability to induce Group3 MB in mice. Surprisingly, concomitant overexpression of c-Myc and other transcription factors in mouse cerebellum is able to induce MB in a few months. The newly generated mouse model is able to fully recapitulate human Group 3 MB. Using this proposed patient-specific model, we were able to unravel the molecular aspects of Group 3 medulloblastoma tumorigenesis and identify molecules inhibiting tumor growth in a targeted manner.