High plasma lipid levels form a prerequisite for the development of atherosclerosis. The recruitment of monocytes to the arterial wall is initiated by the local environment which must be modulated by lipidomic factors. Once monocytes in the arterial wall are converted to macrophages, deposition of excessive amounts of cholesteryl esters, leading to foam cell formation can be considered as a key event in the progression of atherogenesis. Macrophage cholesterol homeostasis involves a delicate balance between lipid influx and lipid efflux. Macrophages are incapable of limiting the uptake of lipids via scavenger receptors and therefore largely depend on cholesterol efflux pathways to maintain cellular lipid homeostasis. Important mediators of macrophage cholesterol efflux are ABCA1, which mediates the efflux of cholesterol to lipid-poor apo A-I. Furthermore ABCG1 and SR-BI can efflux cholesterol to mature HDL. As a consequence of compensatory mechanisms, the single ABCA1, ABCG1 or SR-BI deficiency in macrophages only leads to moderate effects on cholesterol efflux and atherogenesis. Combined deletion of ABCA1 and ABCG1 leads to massive lipid accumulation and foam cell formation of tissue macrophages, while massive foam cell formation, atherosclerotic lesion development and inflammation is also observed by combined deletion of macrophage ABCA1 and SR-BI. The combined macrophage deletions of ABCA1, ABCG1 and/or SR-BI show the essential function of these cholesterol transporters in macrophage foam cell formation and atherosclerotic lesion development. An enhancement of sytemic inflammation markers does accompany the extend of foam cell formation and the interaction between lipid accumulation and the inflammatory status might form an important factor for the pathological events during atherogenesis.