Heterogeneity Medulloblastoma (MB) is the most common malignant brain tumor in children. Standard treatment for MB includes the use of whole brain irradiation to protect against the development of metastasis. Despite this treatment, 30-40% of patients will eventually relapse with terminal metastatic disease, and for the majority of long-term survivors, the radiation therapy employed causes permanent and debilitating neuro-cognitive toxicity. Identifying more effective and less toxic therapy is thus critical for children diagnosed with MB. To achieve this goal, it will be necessary to decipher the complex molecular mechanisms that are essential for MB progression and metastasis to occur. Our lab first described high levels of the PDGFR gene in association with metastatic MB, and for the last decade we have been working on identifying additional key molecular alterations that together are essential for metastasis. Using mouse models of metastatic MB, we most recently found that some genetic changes, such as PDGFR, are present in both the primary and metastatic tumors, while others are confined to the metastases. We therefore hypothesize that “metastasis-driving” molecular alterations emerge within a small subset of cells (“cancer stem-like cells”) within the primary tumor, but are only detectable once these cells are amplified by proliferation during the formation of the metastatic lesions. We thus believe that the cancer cell type and candidate genetic alterations essential for human MB metastasis can be identified by comparing the cells and genetic profiles of the primary tumors and their matched metastases obtained from the same individual in order to better tailor therapy for the prevention and treatment of metastasis.