Elliptocytes from patients with hereditary elliptocytosis (HE) form elliptical ghosts and membrane skeletons. The composition of HE skeletons is quantitatively normal; however, in some but not all kindreds the major membrane skeletal protein, spectrin, is abnormally heat-sensitive, presumably due to a molecular defect which diminishes its conformational stability. Red cells from four mutants of the common house mouse (Mus musculus) with severe, recessive hemolytic anemias show marked membrane budding, fragmentation, and spherocytosis, which suggest membrane instability. Ghosts spontaneously vesiculate and are spectrin-deficient. The amount of spectrin varies from none to one-half the normal amount and correlates with the clinical severity of the four mutations. The cause of this deficiency remains to be determined. These mutants prove that spectrin is a critical determinant of membrane structural integrity and provide a unique opportunity to test, in intact red cells, putative functions of spectrin. Spectrin extracted from ghosts at low ionic strength is heterogeneous. At physiologic ionic strengths part (46 +/- 5%) is polymerized (P-spectrin) and complexed with actin, and part remains as nonpolymerized spectrin dimers and tetramers (NP-spectrin). We postulate that these are native membrane species which exist in a metabolically controlled equilibrium in vivo and that the proportion of these species regulates membrane shape, strength, and flexibility.