Summary: Our understanding of the relationship between the proatherogenic activities of arterial mast cells (MCs) and the development of atherosclerotic lesions is advancing. Atherosclerosis is a chronic inflammatory disease in which cholesterol and other lipids of circulating low-density lipoprotein (LDL) particles accumulate both extracellularly and intracellularly in the innermost layer of the arterial wall, the intima. One prerequisite for the proatherogenic activity of the LDL particles is their retention and proteolytic modification within the extracellular matrix of the intima. Experimental studies with activated chymase-secreting MCs have provided us fundamental insights into the molecular mechanisms of these processes. High-density lipoprotein (HDL) particles, again, remove cholesterol from the intracellular stores and carry it back to the circulation. MC chymase and tryptase actively degrade HDL and thus generate functionally defective particles that are unable to initiate cholesterol efflux from the arterial wall. In advanced atherosclerotic plaques, the accumulated lipids are separated from the circulation by a collagenous cap. By inducing apoptosis of endothelial cells (ECs), subendothelial MCs may induce detachment of ECs from the cap (plaque erosion). Moreover, MCs may weaken the cap if they disturb local collagen turnover by inducing apoptosis of the collagen-secreting smooth muscle cells or when they promote collagen degradation by activating matrix metalloproteinases. Plaques with a weak cap are vulnerable to rupture. The exposed subendothelial tissue at eroded and ruptured sites of plaques triggers local development of a platelet-rich thrombus. As regulators of the collagen-induced platelet activation and fibrin formation/fibrinolysis, the MCs may retard or accelerate the growth of the plaque-associated thrombus and ultimately participate in the wound-healing response of the injured plaque. We propose that by promoting cholesterol accumulation and plaque vulnerability and by locally regulating hemostasis, MCs in atherosclerotic lesions have the potential to contribute to the clinical outcomes of atherosclerosis, such as myocardial infarction and stroke.