Background: Despite the historical focus on cell proliferation in atherosclerosis, advanced plaques are characterized by vascular smooth muscle cell (VSMC) senescence, apoptosis, persistent DNA damage and activation of the DNA damage response (DDR). Methods and Results: Using a series of mouse models, we find that VSMC senescence is regulated by DNA damage and repair, and promotes features of vulnerable plaques, including reduced fibrous cap thickness and expansion of the necrotic core. VSMC senescence may also promote medial degeneration, aneurysm formation and ongoing inflammation. We show that oxidative stress regulates both telomere dependent and independent senescence, and senescence is inhibited by DDR proteins and sirtuins. Mitochondrial DNA damage occurs early in atherosclerosis, and can also promote both VSMC senescence and atherosclerosis. Conclusions: VSMC senescence directly promotes atherosclerosis and medial degeneration, mediated through nuclear and mitochondrial DNA damage