Atherosclerosis is an extremely complex process that involves the interaction of a large number of genes as well as environmental factors: a chronic inflammatory cascade that can be converted to an acute clinical event by the induction of plaque rupture, which, in turn, leads to thrombosis. What are the basic mechanisms that induce this sequence of events? For many years, atherosclerosis research concentrated on the role played by circulating lipids. Many clinical trials have demonstrated that interventions aimed at lowering lipid levels have beneficial effects in terms of reduction in the incidence of cardiac events and in mortality from coronary artery disease. To account for these clinical benefits that have been observed even with relatively short periods of intervention, several hypotheses, such as halting plaque progression and stabilizing rupture-prone lesions, have been suggested. The mechanisms responsible for these observations, however, remain poorly understood. This review focuses on 1) identifying the different lipid components that interact with the vessel wall, 2) defining the different endothelial lipoprotein receptors that bind and transfer the lipid into the cell, and 3) explaining the mechanisms of lipid atherogenicity.