Our understanding of medulloblastoma biology has increased dramatically over the past decade, in part a result of the recognition that there exists tremendous intertumoral heterogeneity not apparent by morphology alone. A particular area that significantly changed our approach to medulloblastoma has been an increased understanding of the role of p53. A role for p53 in medulloblastoma has been established over the past 20 years, however, not until recently has its significance been identified. Recent developments in the understanding of intertumor heterogeneity has clarified the role of TP53 mutations, as the importance of TP53 mutations is highly dependent on the molecular subgroup of medulloblastoma, with TP53 mutant Sonic Hedgehog medulloblastomas forming an extremely high-risk group of patients. As such, there is now a tremendous push to understand the role that p53 plays in treatment resistance of medulloblastoma. In this review, we will summarize the current understanding of p53 in medulloblastoma drawn primarily from recent advances in integrated genomics.