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A decline in the function of the macro- and micro-vasculature occurs with ageing. DNA damage also accumulates with ageing, and thus DNA damage and repair have important roles in physiological ageing. Considerable evidence also supports a crucial role for DNA damage in the development and progression of macrovascular disease such as atherosclerosis. These findings support the concept that prolonged exposure to risk factors is a major stimulus for DNA damage within the vasculature, in part via the generation of reactive oxygen species. Genomic instability can directly affect vascular cellular function, leading to cell cycle arrest, apoptosis and premature vascular cell senescence. In contrast, the study of age-related impaired function and DNA damage mechanisms in the microvasculature is limited, although ageing is associated with microvessel endothelial dysfunction. This review examines current knowledge on the role of DNA damage and DNA repair systems in macrovascular disease such as atherosclerosis and microvascular disease. We also discuss the cellular responses to DNA damage to identify possible strategies for prevention and treatment.