Cholesteryl-ester-loaded macrophages, or foam cells, are prominent features of atherosclerotic lesions and undoubtedly play important roles in lesion development. Foam cell formation involves the uptake of atherogenic lipoproteins or other cholesterol-rich particles by pathways that are down-regulated incompletely or not at all by cholesterol. In addition, postreceptor events that affect intracellular cholesterol metabolism play a critical role in foam cell formation. Increasing evidence shows that the ability of lipoproteins to stimulate cholesterol esterification is dependent upon a regulated and complex pathway that most likely involves one or more proteins in addition to the cholesterol esterifying enzyme itself. The molecular characterization of these proteins, as well as the study of intracellular cholesterol metabolism in vivo, represent important goals for our further understanding of foam cell biology and atherogenesis.