Genomic havoc from one fateful mistake Many human tumors display scrambled genomes that arise from two distinct mutational processes. The first, the chromosome breakage-fusion-bridge (BFB) cycle, produces gene amplification and genomic instability. The second, chromothripsis, generates massive, clustered genomic rearrangements in one or a few chromosomes. Umbreit et al. hypothesized that these two processes are mechanistically related and tested this idea by recreating essential steps of the BFB cycle in cultured cells (see the Perspective by Paiano and Nussenzweig). They found that chromothripsis arises from a cascade of events that begins with aberrant chromosome bridge formation during mitosis, followed by chromosome fragmentation, DNA damage, chromosome missegregation, and the formation of micronuclei. They propose a model that explains how a single cell division error (chromosome bridge formation) can generate many hallmark features of cancer genomes. Science , this issue p. 240 ; see also p. eaba0712