PROJECT SUMMARY Medulloblastoma is the most common malignant brain tumor in children. Although aggressive treatments have improved outcomes, many patients still die of their disease, and survivors suffer severe long-term side effects from the therapy. Thus, safer and more effective approaches to therapy are critical. In our previous studies we have created new animal models of medulloblastoma and used them to define cells of origin, identify key regulators of tumor initiation and maintenance, and uncover agents that may be effective for therapy of the disease. Although we have made important strides over the last few years, there are a number of critical questions that remain unanswered. In the coming years, we will take advantage of the models and approaches we have developed to: (1) Identify drivers and create models for the deadliest forms of medulloblastoma; (2) Uncover the molecular mechanisms of leptomeningeal metastasis, and find novel strategies for targeting metastatic disease; (3) Use primary patient tumors as a platform to discover new therapies; and (4) Identify mechanisms that regulate immune responses to medulloblastoma. The overall goal of our research is to gain a deeper understanding of medulloblastoma biology and use this information to develop more effective approaches to therapy. Although these studies are ambitious, they are essential if we are to make a difference in the lives of children with this devastating disease.