In the past three decades, the survival for patients with medulloblastoma has improved remarkably. Contemporary "standard" therapy for children with medulloblastoma consists of maximal surgical resection followed by craniospinal irradiation with a boost to the posterior fossa, combined with adjuvant chemotherapy. The use of such multimodal therapeutic approaches results in progression-free survival (PFS) rates of 75% to 80% for patients with average-risk disease and approximately 60% for high-risk patients. However, despite the marked improvements in survival, many therapeutic challenges remain. Children with macroscopic metastatic disease (M2/M3) at presentation continue to fare poorly, with the best reports only attaining PFS rates up to 40%. Furthermore, despite intensive multimodal therapy, some patients have disease progression or recurrence, which for most remains incurable. The early recognition of these patients is imperative in order to institute treatment modifications, such as intensification and/or the use of novel experimental therapies. Additionally, the price for cure is clearly evident in survivors, who suffer from significant, often debilitating long-term neurocognitive and neuroendocrine sequela. Using the current clinical stratification system, a significant number of patients are overtreated and unnecessarily subjected to these long-term toxicities. This group of patients would benefit from reductions in therapy. Refinements in patient stratification and further improvement in outcome are unlikely to be achieved without improved knowledge of tumor biology. Several molecular alterations have already been identified, many of which appear to have prognostic significance. Furthermore, the disruption of molecular alterations in signaling pathways involved in the development and maintenance of medulloblastoma using novel molecularly targeted therapies promises to improve outcomes and reduce toxicity for patients with medulloblastoma. It is envisaged that in the near future children diagnosed with medulloblastoma will be more accurately stratified based on a combination of clinical variables and molecular profiles. Improved risk stratification will permit delivery of individualized therapy using conventional treatment modalities in conjunction with novel targeted therapeutic approaches.