Aging is a complex process of damage accumulation causing a functional decline. Several hallmarks of aging have been identified, of which, genomic instability plays a critical role in aging and age-related diseases and closely interacts with other hallmarks of aging. The genome is constantly challenged by exogenous DNA damaging sources, such as ionizing radiation, ultraviolet, and chemicals. But also, endogenous DNA damage caused by alkylation and hydrolysis can lead to chromosomal aberrations, mutations, and epimutations, eventually causing genomic instability and cellular dysfunction. The stressor-induced alterations include chromosomal (chromosome aneuploidy, chromosomal rearrangements, and fragile sites), genomic (increased genetic variability and mutated nucleic acid sequences), replicative (replication stress), and transcriptional impairments. In response to these damages, a wide range of sophisticated repair mechanisms have evolved to repair different types of damage to preserve genomic integrity, such as proper chromosome segregation, efficient DNA damage repair, and faithful DNA replication, to maintain normal function and promote organismal survival. Mammalian DNA damage response systems mainly comprise nonhomologous end joining, homologous recombination, nucleotide excision repair, base excision repair, mismatch repair, direct reversal repair, and translesion DNA synthesis. To ensure genomic stability there is crosstalk and redundancy between the different DNA repair pathways.