Aging is a complex phenomenon that involves the gradual decline of biochemical, cellular and physiological functions, ultimately concluding with the demise of the organism. While many theories have been proposed for why and how we age, evidence supports a model whereby the slow accumulation of stochastic macromolecular damage eventually leads to dysfunction and death. In particular, genetic material, the master blueprint for most biological systems and operations, is a major target of intrinsic and extrinsic genotoxic agents. Consequent DNA damage can accumulate over one's lifetime, resulting in altered genomic landscapes and regulatory networks, mutagenic events, chromosome instability, and adverse cellular outcomes, such as transformation, apoptosis and senescence, which underlie premature aging phenotypes, disease and an abbreviated lifespan. We review in this chapter the evidence that DNA damage, specifically to the nuclear genome, and the mechanisms that preserve DNA integrity (i.e., DNA repair) are key factors in the aging process.