Modification with UFM1 (UFMylation) has recently emerged as a versatile signaling system regulating diverse cellular processes, from endoplasmic reticulum homeostasis to genome stability. Recent studies have expanded this landscape by revealing a direct role of UFMylation in the core machinery of DNA replication. Specifically, UFMylation of MCM5 is required for optimal activation of the CDC45–MCM–GINS (CMG) helicase, the molecular engine that governs origin firing and drives replication fork progression. This discovery introduces a previously unrecognized regulatory layer into the DNA replication program and positions UFMylation as an important coordinator of genome duplication, whose disruption provides a mechanistic explanation for developmental disorders such as microcephalic primordial dwarfism (MPD), while more subtle or progressive dysregulation may have important implications for genome stability across ageing and cancer.