Major risk factors for clinical atherosclerosis include dyslipidemia, hypertension, glucose intolerance, adiposity, cigarette smoking, hemostatic factors, inflammatory markers, and sedentary lifestyle. Sets of some of these and evidence of vascular damage such as left ventricular hypertrophy and atrial fibrillation are used to formulate multivariable risk profiles for peripheral artery disease and stroke. These global risk formulations facilitate office estimation of the risk of these disabling diseases, which often indicate diffuse systemic atherosclerosis. Because predisposing risk factors usually cluster, and the risk each imposes varies widely, global risk assessment is a necessity, especially now that average risk factor levels are recommended for treatment. Novel risk factors deserve attention, but the standard cardiovascular risk factors account for as much as 85% of the cardiovascular disease arising within the population. Further improvement in detection, evaluation, and control of the major risk factors by implementation of guidelines for primary and secondary prevention of stroke and peripheral artery disease is needed, particularly in the high-risk segment of the population.