Monocytes/macrophages are physiological cellular components of the subendothelium of greater arteries as has been shown by our studies on endothelial/intimal preparations of 9 species, including man. Differentiation is possible between species rich (pig, man, sheep) or poor in macrophages (rabbit and other small laboratory animals) according to their density of subendothelial infiltration in the aorta. Morphological, histochemical, and ultrastructural results have shown that we are mainly dealing with metabolic quiescent, resident macrophages, their number being regulated by influences depending on endothelium and intima factors. We assume that in species rich in macrophages and in man, they have physiological functions for homoeostasis of border layer and intima. The most considerable signal for subendothelial macrophage accumulation in man, pig, and rabbit is intimal deposition of lipids, independent of experimental or spontaneous induction. Short-term or long-term hypercholesterolemia is not associated with increased adhesion and emigration of monocytes in unchanged intima at venous or arterial endothelial cells of pigs and rabbits. There is no evidence to intimal lipid infiltration being preceded by subendothelial macrophage invasion. Most studies on vessel border layer have suggested that in the early high-lipid phase of atherogenesis subendothelial macrophages participate in lipid metabolic clearance. But in conditions of metabolic activation they can be an atherogenic danger due to a whole range of secretory products stimulating recruitment of blood monocytes and lymphocytes, increasing the permeability of endothelium, altering the extracellular matrix components, and causing modulation of gen expression of vessel wall cells. Therefore, metabolic activation of the subendothelial macrophage system is a new, potentially atherogenic mechanism.