Medulloblastoma is a cerebellar tumor affecting children and young adults, and accounts for approximately one fifth of all pediatric brain tumors. Despite multimodal therapy that includes surgery, radiotherapy and chemotherapy, recurrence is frequent and overall mortality rate remains relatively high. Moreover, radiation therapy results in severe effects on intellect, and younger age of treatment correlates with larger deficits. Improvements in therapy of this childhood tumor will focus increasingly on the clarification of the exact cellular origin and the genetic mechanisms contributing to tumor formation, and on new targeted therapeutic options. Aberrant activation of the Hedgehog (Hh) and Wnt developmental pathways is associated with medulloblastoma, but deregulation of other molecular pathways, including insulin-like growth factor (IGF) signaling, has also been implicated in the pathogenesis of the tumor. Recent observations in mouse models have demonstrated the importance of genome surveillance, as defects in DNA repair pathways in animals can lead to genomic instability in neural progenitor cells, resulting in medulloblastoma. The current review will focus on the most recent findings on the molecular pathology of medulloblastoma and discuss their potential contribution to treatments directed by the molecular alterations.