Recent studies involving the anion transport protein AE1 (syn. band 3) and glycophorin C in their normal and variant states have demonstrated that these cytoskeletal associated transmembrane proteins play an important role in maintaining the shape and mechanical properties of the human red blood cell. Mutations in the band 3 molecule can lead to a variable outcome on the integrity and physical properties of the erythrocyte. The band 3 Memphis variants and band 3 high transport, for example, appear to have no deleterious effects on the mechanical properties of the red cell whereas total loss of anion transport activity and increased plasma-membrane rigidity is observed with South-east asian ovalocytes. The mechanisms by which mutant band 3 molecules affect the final properties of the cell appear to result from a missasembled membrane domain and an alteration in the protein’s association with the cytoskeleton. Cell shape changes are commonly observed in band 3 mutant cells, manifested as spherocytes, choreoacanthocytes or acanthocytes. Leach phenotype cells, which lack glycophorins C and D and protein p55, when stripped of protein 4.1, have a much reduced affinity for the binding of purified protein 4.1 than normal protein 4.1 depleted cells. Recent studies have shown that protein 4.1 and protein p55 associate directly and on different sites with glycophorin C and that the glycophorin C-protein 4.1-protein p55 complex is required to maintain the shape and mechanical properties of the red cell.