It is proposed that stiffened red cells can interfere with normal microvascular and glomerular function. In diabetics intrinsic stiffening of red cells is intensified during poor metabolic control when plasma osmolarity is increased. Hypoxia, acidosis, catecholamines and other changes in red cell environment also increase red cell stiffness. Exercise proteinuria may help to identify individuals with the greatest intrinsic stiffening of red cells which appears to be due to the disposition of spectrin molecules rather than to changes in the lipid bilayer. Stiffened red cells may impede blood flow in the microcirculation and stimulate an autoregulated vasodilation which increases perfusion pressure, enhancing transudation. In the absence of vasodilation, stasis will lead to vascular occlusion and localised ischaemic necrosis. If diabetic microangiopathy is caused by abnormal haemorheology then the possibility exists that the complications of diabetes might be alleviated or prevented by agents which enhance red cell flexibility and improve blood rheology.