Oxidative stress affects the availability of key-regulators of vascular homeostasis and controls a number of signaling pathways relevant to myocardial and vascular disease. Reactive oxygen species are generated by different intracellular molecular pathways principally located in mitochondria. The notion that mice carrying a targeted mutation of the p66^Shc gene display prolonged lifespan, reduced production of intracellular oxidants, and increased resistance to oxidative stress–induced apoptosis prompted a series of studies aimed at defining the biochemical function of p66^Shc and its possible implication in cardiovascular diseases. Indeed, p66^Shc−/− mice are protected against vascular, cardiac, and renal impairment attributable to hypercholesterolemia, aging, diabetes, and ischemia/reperfusion. The present review focuses on the biochemical and physiological function of the p66^Shc adaptor protein as well as on the mechanisms linking p66^Shc-associated generation of free radicals to the pathophysiology of aging and cardiovascular disease. On the whole, the evidence so far reported and here discussed supports the concept that pharmacological modulation of p66^Shc expression and activity may be a novel and effective target for the treatment of atherosclerotic vascular disease as well as myocardial adaptation to hypertrophic, inflammatory and neuro-hormonal stimuli in the overloaded heart.