Similar to apoptosis of nucleated cells, erythrocytes may undergo eryptosis, a suicidal death characterized by cell shrinkage and phospholipid scrambling of the cell membrane leading to phosphatidylserine exposure at the cell surface. As eryptotic erythrocytes are rapidly cleared from circulating blood, excessive eryptosis may lead to anemia. Moreover, eryptotic erythrocytes may adhere to the vascular wall and thus impede microcirculation. Stimulators of eryptosis include osmotic shock, oxidative stress and energy depletion. Mechanisms involved in the stimulation eryptosis include ceramide formation which may result from phospholipase A2 dependent formation of platelet activating factor (PAF) with PAF dependent stimulation of sphingomyelinases. Enhanced erythrocytic ceramide formation is observed in fever, sepsis, HUS, uremia, hepatic failure, and Wilson's disease. Enhanced eryptosis is further observed in iron deficiency, phosphate depletion, dehydration, malignancy, malaria, sickle-cell anemia, beta-thalassemia and glucose-6-phosphate dehydrogenase-deficiency. Moreover, eryptosis is triggered by osmotic shock and a wide variety of xenobiotics, which are again partially effective by enhancing ceramide abundance. Ceramide formation is inhibited by high concentrations of urea. As shown in Wilson's disease, pharmacological interference with ceramide formation may be a therapeutic option in the treatment of eryptosis inducing clinical disorders.