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Alterations in the transbilayer distribution of phospholipids in the erythrocyte membrane have significant physiologic consequences. Understanding the cause of these perturbations and the molecular mechanisms by which they are regulated is essential for ameliorating some of the consequences of erythrocyte membrane abnormalities. This review summarizes recent data that provide a clearer description of the molecular events involved in these processes.Proteomic and molecular evidence supports the presence of a small number of lipid transporters that control the distribution of phospholipids across the erythrocyte membrane. These include members of the ATP-binding cassette and P-type ATPase transporter families. Recent data indicate that these proteins work in synergy and may require additional protein partners. Growing evidence illustrates the critical role these transporters play in the maintenance of lipid asymmetry and the central role that oxidative damage plays in the membrane perturbing effects of some cardiovascular diseases.Recent publications have added further clarity to the processes that control phospholipid asymmetry in erythrocytes and the mechanisms by which diseases affect lipid distribution. Transmembrane transporters regulate the organization of phospholipids across the bilayer, and oxidative damage induced by disease states may be a common perturbant of phospholipid asymmetry.