Hypertension, dyslipidemia, and glucose intolerance cocluster in the population and act synergistically in increasing coronary artery disease risk. The mechanisms by which these risk factors interact in atherosclerosis are complex. First, hypertension, dyslipidemia, and altered insulin sensitivity may have a common pathophysiological basis. Activation of neurohormonal mechanisms may be implicated in many or all of these processes. In addition, underlying these processes may be common genetic and environmental influences. Second, these risk factors ultimately act on the blood vessel, thereby leading to atherosclerosis. Elevated serum lipids lead to vessel wall responses, including endothelial dysfunction, smooth muscle cell proliferation, lipid accumulation, foam cell formation, and, eventually, necrosis and plaque development. Hypertension may induce shear-related injury to the vessel. Endothelial injury (caused by hypertension) and vascular cell proliferation (induced by increased pressure and/or vasoactive substances) are effects that amplify the atherosclerotic process. In addition, diabetes and hyperinsulinemia can increase vascular tone, impair endothelial function, and stimulate vascular smooth muscle cell proliferation. Control of these risk factors should prevent or attenuate the vessel wall responses. Emphasis is now being placed on pharmacological therapeutic modalities that decrease blood pressure and improve insulin sensitivity and lipid metabolism. Identification of common links between risk factors, such as neurohormonal mechanisms (e.g., angiotensin), should lead to better therapeutic strategies.