<p>Medulloblastoma, the most common malignant brain tumor of childhood, is an aggressive embryonal tumor that arises from the posterior fossa. On the molecular level, four clinically relevant subgroups have been established, which have already been integrated into routine diagnostic procedures and treatment stratification. The initial step in treating medulloblastoma typically involves maximal safe surgical resection, followed by craniospinal irradiation in most patients (except very young children) and chemotherapy. Efforts to improve cure rates and reduce long-term detrimental effects led to the reduction in radiotherapy and adaptation of chemotherapy. Gradually, over the past decades, these strategies have resulted in significant improvements in treatment outcomes. However, patients with a medulloblastoma recurrence still fare badly, especially those children who already had radiotherapy as part of their initial treatment. Whereas there is no universal treatment strategy at relapse and the outcome remains poor, recently, the administration of anti-angiogenic metronomic therapy led to sustained long-term survival in a quarter of patients. Nonetheless, there remains an unmet need to improve survival and mitigate therapy-induced morbidity by developing new treatment strategies. Promising new approaches include targeting the Sonic Hedgehog pathway, addressing transcriptional and epigenetic drivers, improving drug delivery, and overcoming treatment resistance. Although the most common malignant brain tumor of childhood, the number of novel approaches in addition to a molecularly subdivided entity renders it difficult to form large clinical trials.</p>