The factors which normally limit the life of the red cell are described as being a continuous metabolic process involving the enzymatic oxidation of Hb and a terminal event, which may be hemolysis, fragmentation or phagocytosis. A number of lytic substances, such as soaps, lipids and lysolecithin-like substances can be extracted from plasma and from tissues. These substances are associated with inhibitors and accelerators to form complexes. The activity of these naturally occurring hemolytic complexes tends to be small, although it can increase to such an extent that appreciable red cell destruction results. Instances are given in which hemolysis in vivo results from the concentration of one of these lysins increasing (as when fat is fed), from an accelerator of one of the lysins being introduced (usually as a drug), and from the concentration of inhibitory material being reduced (as by a low cholesterol diet). Most hemolytic episodes are due to the establishment of a new hemolytic mechanism, which may appear after the introduction of a drug, of an agglutinin such as silicic acid or ricin, of an immune agglutinin which is not itself a hemolysin or of an agglutinin which is a lysin in the presence of complement. The various mechanisms which may result in hemolysis are discussed. The case in which the agglutinin becomes a lysin in the presence of complement presents no difficulty; in other cases the mechanism of hemolysis is not so clear, nor is it clear whether red cell destruction depends primarily on hemolysis or primarily on phagocytosis. Special processes are involved in the destruction of red cells which have intrinsic defects of structure. The abnormally thick red cells of congenital hemolytic icterus are selectively sequestered in the spleen, where there are a number of hemolytic mechanisms which can destroy them the more readily because of their abnormal shape. The sickle cell, with its poor osmotic properties, its reduced mechanical fragility, and its tendency to lose part of its structure as filaments at each disk-sickle transformation, is destroyed by processes which are probably hemolytic but less easy to specify. The flat red cells of Mediterranean disease are abnormally prone to fragmentation. In all these diseases the abnormal shape of the red cell seems to be accompanied by peculiarities in its contained hemoglobin, an observation which requires further study before its significance is clear.