DNA over-replication is a phenomenon that can have devastating consequences for proliferating cells. When parts of the genome are duplicated more than once, cells suffer from ‘genomic instability’ (alterations to the structure, composition and/or number of chromosomes), and this process gives rise to aberrant cells as those detected in many carcinomas. The cooperation of two proteins called CDC6 and CDT1 is essential for normal DNA replication but when they are not properly regulated, the genetic material replicates in excess. A paper published in Cell Reports by the DNA Replication Group of the Spanish National Cancer Research Centre (CNIO) sets out the fatal consequences of in vivo re-replication for the first time in mammalian organisms.