Increasing research interest has focused on arterial calcification in the setting of atherosclerosis. Many features of atherosclerosis-related calcification provide useful clinical information. For example, calcium mineral deposits frequently form in atherosclerotic plaque, and intimal arterial calcification can be used as a surrogate marker for atherosclerosis; also, calcium deposits are readily and noninvasively quantified, which is useful because greater amounts of coronary calcification predict a higher risk of myocardial infarction and death. Several mechanisms leading to calcification associated with atherosclerosis have been proposed; however, no direct testing of proposed mechanisms has yet been reported. Studies in genetically altered animals and in humans have shed light on potential genetic determinants, which in turn could form the basis for a more comprehensive understanding of the factors affecting calcification within plaque and the associated pathobiologic implications. We review proposed molecular and cellular mechanisms of atherosclerosis-associated arterial calcification, summarize genetic influences, and suggest areas in which further investigation is needed. Understanding the molecular and genetic determinants of specific structural plaque components such as calcification can provide a solid foundation for the development of novel therapeutic approaches to favorably alter plaque structure and minimize vulnerability to arterial rupture.