Maintaining the stability of the genome is essential for all organisms, and it is not surprising that damage to DNA has been proposed as an explanation for multiple chronic diseases.1-5 Conserving a pristine genome is therefore of central importance to our health. To overcome the genotoxic stress that occurs as part of daily living, several DNA-repair pathways have evolved. In general, DNA repair is organized within intricate enzymatic networks that deal with particular chemical reactions involving DNA.6,7 Most DNA-repair pathways are characterized by three steps: detection of the DNA modification (or modifications), removal or further modification of the damaged DNA, and resynthesis of the missing nucleotides and ligation of DNA strands. The majority of DNA-repair pathways are highly conserved from bacteria to humans, and inherited defects in DNA repair have been identified as the underlying cause of a growing number of human diseases. Notably, many of these monogenic DNA-repair disorders display features of accelerated aging, supporting the notion that genome maintenance is a key factor for organismal longevity. This review focuses on the physiological consequences of loss of DNA repair, particularly in the context of monogenic DNA-repair diseases.