Medulloblastoma comprises four distinct molecular variants. This study analyzed 103 primary medulloblastomas to determine the number of subgroups, their differences, and overlap. Using gene expression profiles and DNA copy number aberrations, four distinct subgroups were identified: WNT, SHH, group C, and group D. These subgroups showed significant differences in demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for subgroup-specific signature genes reliably classified tumors in approximately 98% of patients. Group C tumors had significantly reduced progression-free and overall survival regardless of metastatic status. The study's integrative genomics approach identified four subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcomes. Medulloblastomas can be reliably classified using immunohistochemistry, making subclassification widely available. Future research and clinical trials should consider these four subtypes. The study also highlights the importance of molecular classification for accurate patient stratification, improved clinical trial design, and the development of molecularly targeted therapies. The four subgroups are distinct in terms of demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcomes. The study's findings suggest that targeted therapies may need to be developed for each subtype individually due to their biological differences. The results emphasize the need for further research into the cellular origin and specific genetic events in each subgroup to determine if they represent four distinct diseases.Medulloblastoma comprises four distinct molecular variants. This study analyzed 103 primary medulloblastomas to determine the number of subgroups, their differences, and overlap. Using gene expression profiles and DNA copy number aberrations, four distinct subgroups were identified: WNT, SHH, group C, and group D. These subgroups showed significant differences in demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for subgroup-specific signature genes reliably classified tumors in approximately 98% of patients. Group C tumors had significantly reduced progression-free and overall survival regardless of metastatic status. The study's integrative genomics approach identified four subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcomes. Medulloblastomas can be reliably classified using immunohistochemistry, making subclassification widely available. Future research and clinical trials should consider these four subtypes. The study also highlights the importance of molecular classification for accurate patient stratification, improved clinical trial design, and the development of molecularly targeted therapies. The four subgroups are distinct in terms of demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcomes. The study's findings suggest that targeted therapies may need to be developed for each subtype individually due to their biological differences. The results emphasize the need for further research into the cellular origin and specific genetic events in each subgroup to determine if they represent four distinct diseases.