Common fragile sites (CFSs) are chromosomal regions that are prone to form breaks or gaps during mitosis, in particular following replication stress. The mechanisms modulating CFS expression and promoting safe chromatid transmission to daughter cells are not clear. Now CFS expression is shown to reflect the activity of the MUS81–EME1 resolvase complex which cooperates with the dissolving action of the BLM helicase to prevent uncontrolled chromosome breakage and to promote genome integrity.