A defined role in the atherogenic sequence is proposed for the circulating monocyte. The author has been able to demonstrate a" monocyte clearance system" in which large numbers of circulating monocytes invade the intima of lesion-prone areas in arteries, become phagocytic, and accumulate lipid. A fatty cell lesion results. Once lipid-laden, foam cells migrate back into the bloodstream by crossing the arterial endothelium. The ratio of penetrating monocytes to emerging foam cells decreases as fatty cell lesions develop until a one-to-one ratio is achieved in late fatty cell lesions, which do not progress further. Advanced fibroatherosclerotic plaques in the same animals do not show the same characteristics and have smooth muscle cell involvement. It would appear that advancement of the lesion is at least partially a result of failure of the monocyte clearance system to remove sufficient lipid. The invasion of monocytes and endothelial damage caused by foam cell clearance may, in late fatty lesions, contribute to plaque evolution by introducing growth factors from macrophages and platelets and allowing greater lipid influx. Elucidation of this system was facilitated by the examination of vessels from diet initiation onwards and by the observation of late nonprogressing fatty cell lesions. It is possible that this system exists in other models but has been overlooked by a predilection for the study of advanced lesions that prevails in the literature.