A schematic representation of the human red cell membrane. The membrane is a composite structure of a lipid bilayer anchored to a two-dimensional elastic network of skeletal proteins through ankyrin- and protein 4.1–based transmembrane protein complexes embedded in the lipid bilayer. Deficiency in any of the proteins involved in the vertical linkages involving the ankyrin complex leads to loss of cohesion between the lipid bilayer and membrane skeleton and the resultant loss of membrane surface area. The horizontal linkages between spectrin-spectrin dimers and between spectrin-actin-protein 4.1R in the junctional complex determine red cell membrane mechanical integrity. Defective horizontal linkages lead to decreased integrity of the membrane mechanics and cell fragmentation. Reproduced with permission from Mohandas and Gallagher.