Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. Display omitted ► Complex chromosomal alterations (chromothripsis) observed in medulloblastomas ► Cancers with such alterations harbor TP53 mutations ► Context-specific link between the status of p53 and likelihood of chromothripsis ► p53 status and chromothripsis also correlate with aggressive acute myeloid leukemia Connecting p53 status and chromothripsis in specific types of cancer provides a genetic basis for the more aggressive forms of medulloblastoma and leukemia.