Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Very little is known about aggressive forms of this disease, such as metastatic or recurrent MBs. In order to identify pathways involved in aggressive MB pathophysiology, we performed unbiased, whole genome microarrays on MB tumors at both the human and murine levels. Primary human MBs were compared, transcriptomically, to their patient-matched recurrent or metastatic tumors. Expression profiling was also performed on murine tumors from two spontaneously developing MB mouse models (Ptch+/- and Smo/Smo) that present with differing clinical severities. At both the human and murine levels we identified transforming growth factor-beta (TGF-β) as a potential contributor to MB progression/metastasis. Smad3, a major downstream component of the TGF-β pathway, was also evaluated using immunohistochemistry in malignant human tissues and was shown to correlate with MB metastasis and survival. Similarly, Smad3 expression during development identified a subset of cerebellar neuronal precursors as putative cells of origin for the Smad3-positive MBs. To our knowledge, this is the first study that links TGF-β to MB pathogenesis. Our research suggests that canonical activation of this pathway leads to better prognosis for patients.