Although the links between defects in DNA repair and cancer are well established, an accumulating body of evidence suggests a series of functional links between genome maintenance pathways, lifespan regulation mechanisms and age-related diseases in mammals. Indeed, the growing number of DNA repair-deficient patients with progeria suggests that persistent DNA damage and genome caretakers are tightly linked to lifespan regulating circuits and age-related diseases. Here, we discuss the impact of irreparable DNA damage events in mammalian physiology highlighting the relevance of DNA repair factors in mammalian development and aging.