DNA turnover through damage and repair is normal homeostatic process in viable cells. DNA damage induces sequential responses to either repair the damage or activate a programmed cell death process. Defects in this critical response to DNA damage underpin a wide array of human pathologies that include cancer predisposition, immune dysfunction, radiosensitivity, and neurodegeneration. Recent experimental and clinical studies have suggested that oxidative stress leading to catastrophic DNA damage is enhanced in failing hearts as well as other cardiovascular diseases. Accordingly, targeting the genotoxic effects of oxidative stress may prove to be a novel avenue in the development of rational therapies for cardiovascular diseases. A platform introduction to DNA repair/response are integrated, and insights into the future directions of this exciting field are offered.