The precise molecular defect in hereditary spherocytosis (HS) remains unknown. It is generally accepted, however, that the underlying membrane defect is the cause of the rigidity, shape, and permeability abnormalities of HS red cells. The spleen, with its unique microcirculation, plays the key role in the pathophysiology of hereditary spherocytosis. It is responsible for mechanical sequestration of spherocytes in the splenic cords, it is responsible for phagocytosis of spherocytes and their breakdown products, and it is responsible for the deleterious “conditioning” of those red cells which manage to escape back into the general circulation. The role of the spleen in the pathophysiology of the severe hemolytic form of hereditary elliptocytosis appears to be quite similar.