That some membranes restrict certain lipid species to one side of the bilayer and others to the opposite side has been known for two decades. However, how this asymmetric transbilayer distribution is generated and controlled, how many and what type of membranes are so structured, and even the reason for its existence is just now beginning to be understood. It has been a decade since the discovery of an activity which transports in an ATP-dependent manner only the aminophospholipids from the outer to the inner leaflet of the plasma membrane. This aminophospholipid translocase has yet to be isolated, reconstituted, and identified molecularly. Elevating intracellular Ca2+ allows all the major classes of phospholipids to move freely across the bilayer, scrambling lipids and dissipating asymmetry. The nature of this pathway and its mode of activation by Ca2+ remain to be determined. Though loss of transbilayer asymmetry by blood cells clearly produces a procoagulant surface and increases interactions with the reticuloendothelial system, it remains to be elucidated whether maintenance of blood homeostasis is just one expression of a more general raison d'être for lipid asymmetry. It is these persisting uncertainties and gaps in our knowledge which make the field such an interesting and exciting challenge at the present time.