Atherosclerosis, an intrinsically age-related disease, is attributed to an excessive inflammatory and fibroproliferative process that selectively affects arteries. However, premature atherosclerosis is a feature of several human diseases that are known to be defective in DNA repair pathways and characterised by predisposition to early onset of age-related diseases. Accordingly, there is a growing amount of data demonstrating that oxidative-stress-induced DNA damage and dysfunctional telomeres play an important role in the pathogenesis of atherosclerosis. This review examines the evidence that an activated DNA response pathway induced by both oxidative DNA damage and telomere dysfunction is the crucial mediator for vascular replicative or premature senescence via activation of the p21cip1 (via p53) and p16ink4 pathways. Prevention of DNA-damage-induced cellular vascular senescence may be a novel target for the clinical treatment of atherosclerosis.