Accumulation of oxidative stress with age has been documented consistently in tissues of different species and hypothesized to be the primary causative mediator of age-associated diseases. Accumulation of oxidative stress with age is hypothesized to be the primary causative mediator of age-associated diseases. Among different tissues, aging vessels are known to accumulate oxidative damage and undergo functional impairment. Oxidative stress affects the availability and/or balance of key-regulators of vascular homeostasis and favours the development of cardiovascular disease. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria. The mitochondrial enzyme p66^Shc is an adaptor protein and plays an important role as a redox enzyme implicated in mitochondrial ROS generation and translation of oxidative signals into apoptosis. Mice lacking p66^Shc-/- gene display reduced production of intracellular oxidants and a 30% prolonged life-span. For this reasons, a series of studies conceived to elucidate the function of p66^Shc and its possible implication in age-associated cardiovascular diseases have been carried out. Indeed, p66^Shc-/- mice have been shown to be protected from age-dependent endothelial dysfunction as well as age-related risk factors such as diabetes and hypercholesterolemia. This review focuses on delineating the role of the p66^Shc adaptor protein and its potential implication in the pathophysiology of aging and age-related cardiovascular disease.