The asymmetrical organization of phospholipids in the human erythrocyte membrane, discovered by Bretscher (1972) and soon confirmed by other groups (Verkleij et al., 1973; Gordesky et al., 1975), has been followed by 15 years of in-vestigations on the lipid topology in eukaryotic plasma mem-branes and membranes from organelles, bacteria, and viruses. Although the agreement between the different laboratories at a quantitative level is often unsatisfactory, most biological membranes appear to have a different phospholipid compo-sition in their inner and outer leaflets. At least in plasma membranes, transverse lipid segregation is firmly established. In erythrocytes, the best documented system, phosphatidyl-serine (PS), 1 phosphatidylethanolamine (PE), and probably phosphatidyl inositol (PI) are located mainly in the inner monolayer while phosphatidylcholine (PC) and sphingomyelin (SM) are essentially in the outer monolayer. For many years, lipid asymmetry was considered as the natural consequence of the asymmetrical environment of all biomembranes. Knowing that transverse diffusion, or lipid flip-flop, is a slow process, lipid asymmetry was thought to be the consequence of asymmetrical membrane biogenesis and asymmetrical lipid turnover by endogenous phospholipases and reacylases, together with the asymmetrical insertion of lipid constituents. The differences in potential and/or pH between the two surfaces could also explain the stability of the asym-metrical distribution. However, in 1984, the existence of an

ATP-requiring mechanism responsible for the specific translocation of aminophospholipids (PS and PE) was demonstrated in human red cells (Seigneuret & Devaux, 1984) and later in other plasma membranes [for a review, see Devaux (1988)]. Virtually at the same time the rapid redistribution of PC in rat liver endoplasmic reticulum was attributed to a “PC flippase” by Bishopand Bell (1985). Thus, it appeared that living cells had developed elaborate mechanisms to control the