Mast cells have been assigned a role in the development of atherosclerotic lesions and their clinical complications. The mast cells are multipotent effector cells which originate in the bone marrow, circulate as progenitor cells, and ultimately find their ways into various tissues. Like in other tissues, also in the inner layer of the arterial wall, the intima, the progenitor cells remain in the close vicinity of endothelial cells, and slowly differentiate into mature mast cells which are filled with cytoplasmic secretory granules. The granules contain histamine, heparin, and neutral serine proteases tryptase, chymase, and cathepsin G. In addition, the granules contain several growth factors such as bFGF, VEGF, and TGF-beta, and proinflammatory cytokines such as TNF-alpha. Once stimulated, the mast cells degranulate, and so exocytose the effector substances into the immediate surrounding of the activated mast cells. Atherosclerotic lesions develop in the intima. Originally, blood-derived lipids accumulate within intimal macrophages, then the macrophages become converted into foam cells, and fatty streaks develop. Later, the fatty streaks develop into mature atherosclerotic plaques along two principal histopathological pathways: they develop either into inward-growing fibrotic lipid-poor lesions, or into outward-growing non-fibrotic lipid-rich lesions. The former ones cause significant stenosis and local turbulent flow conditions, while the latter ones do not cause such intraluminal changes. Irrespective of the mode of growth, the plaques show signs of inflammation, and may cause atherothrombotic complications, when the subendothelial thrombogenic surface becomes exposed to blood. As a result, an arterial platelet-rich thrombus develops, and may cause myocardial infarction or stroke. The mechanisms of plaque disruption leading to atherothrombotic complications depend on the type of the plaque: a stenosis-causing fibrotic plaque usually erodes, while a non-stenotic lipid-rich plaque typically ruptures. What are the suggested mechanism by which intimal mast cells might contribute to the development of the above-described atherothrombotic events? Regarding erosion, activated subendothelial mast cells secrete proteases which degrade various components of the endothelial basement membrane, and so render the endothelial cells susceptible to physical detachment by the forces exerted by the local turbulent flow of blood. Proteolytic degradation of the pericellular matrix of the endothelial cells may also cause loss of the outside-in survival signaling, which, together with mast cell-derived TNF-alpha induces apoptotic death of the endothelial cells. Support for the mast cell-dependent erosion of coronary artery plaques comes from the observation that coronary microthrombi are often located above subendothelial mast cells. Regarding plaque rupture, following mechanisms have been suggested to be operative in the lipid-rich lesions. In the lipid-rich lesions, a collagen-containing fibrous cap is synthesized and maintained by viable smooth muscle cells (SMCs). The fibrous cap separates the large lipid core from the circulating blood. If activated to degranulate, the mast cells present in the cap do secrete heparin and the neutral protease chymase, which together exert multiple inhibitory actions on their neighboring SMCs. Heparin inhibits growth of SMCs and chymase inhibits collagen synthesis by these cells. By degrading fibronectin of the pericellular matrix of the SMCs, chymase triggers their apoptotic death. Together, these actions by mast cells tend to cease collagen synthesis in the cap. Moreover, the mast cell-derived proteases chymase, tryptase, and cathepsin G, activate matrix metalloproteinases (MMPs), which again, degrade collagen and other components of the extracellular matrix in the fibrous cap. Finally, by secreting TNF-alpha, mast cells stimulate neighboring macrophages to synthesize and secrete pro-MMP-9, which may then be activated in the plaque. The ability of mast cells to simultaneously attenuate matrix synthesis and to accelerate matrix degradation contributes to the local catabolic state within inflamed areas of the fibrous plaque. As a consequence, in these areas the cap becomes thin and fragile, and the lipid-rich plaque becomes vulnerable to rupture.