Various methods have been used to quantify atherosclerosis, beginning in the mid-1980s with ultrasound measurement of carotid intima-media thickness (IMT), and going on to coronary calcification assessed by electron-beam CT, measurement of carotid plaque by ultrasound, and measurement of carotid wall thickness by MRI. In recent years, it has become clear that carotid IMT, coronary calcification and carotid plaque reflect biologically and genetically different aspects of the atherosclerotic process, and will respond differentially to therapy. IMT represents mainly hypertensive medial hypertrophy; this measure is more predictive of stroke than of myocardial infarction, and is only weakly associated with traditional coronary risk factors. Carotid plaque area, on the other hand, is more strongly associated with traditional risk factors, and is more predictive of myocardial infarction than of stroke. A quantitative trait, called 'unexplained atherosclerosis', expresses the extent to which an individual has excess carotid plaque not explained by traditional risk factors, or the extent to which an individual is protected from traditional risk factors. Unexplained progression of plaque is an even more powerful tool for genetic research, because age, which accounts for the greatest proportion of baseline plaque, has much less influence on the rate of progression. Compared with IMT, measurement of carotid plaque volume by three-dimensional ultrasound reduces by two orders of magnitude the sample size and duration of treatment needed to evaluate new therapies. Measurement of carotid plaque is, therefore, an important tool for patient management, genetic research and evaluation of new therapies for stroke prevention.