The normal survival of red cells requires maintained regulation of cell size and shape. This regulation is to a large extent dependent upon membrane permeability and the active transport of cations. Agents such as C' that affect permeability markedly by creating large holes in the membrane lead to rapid cell death. Most hemolytic disorders thus far studied involve lesser increases in membrane permeability and hemolysis occurs more gradually by the sequence of colloid osmotic swelling, loss of cell surface, and spherocytosis. With very mild permeability changes, as in hereditary spherocytosis, the cell may compensate for an increased leak-rate for cations by increased active transport. This compensation requires increased glycolysis and optimal metabolic conditions, however, and the cell rapidly decompensates during glucose deprivation or metabolic stress. The interaction between reticuloendothelial tissues and red cells provides such a stress for leaky cells and hastens their destruction.