There is a considerable body of evidence gathered from studies over the past half a century indicating that a high level of physical activity and a moderately high or high degree of cardiorespiratory fitness reduces the risk of CVD (cardiovascular disease). Recent data suggest that high levels of physical activity or fitness may be particularly beneficial to individuals with insulin-resistant conditions, such as the metabolic syndrome, Type II diabetes or obesity. These individuals, if unfit and sedentary, exhibit increased CVD risk, but their dose-response relationship for physical activity/fitness appears to be particularly steep such that, when they undertake high levels of activity (or have high fitness), their level of risk becomes closer to that of their normal weight or nondiabetic peers. This may be due to effects of physical activity in normalizing the metabolic dysfunction particularly associated with insulin-resistant conditions.