Rheological determinants of pathophysiology of sickle cell disease are analyzed. Basic concepts of blood viscosity and its relationship to cell-cell, cell-protein, and cell-vessel interaction are presented. Viscosity alterations in sickle cell disease are attributed primarily to increased internal viscosity and membrane rigidity of the deoxygenated sickle cell and oxygenated irreversibly sickled cell which interact with capillaries of critical diameter to initiate microvascular occlusion. A critical pO2 of 70 mm of mercury for initial reduction of sickle cell deformability was found. Alterations of microvascular blood flow in sickle cell disease are graphically shown by dynamic microcinematography which demonstrates the abnormal rheology of the sickle cell in a model capillary bed. Entrapment of rigid sickle cells at capillary junctions, reversible sickle cell capillary blockade and microvascular occlusion, and rheologic concomitants are demonstrated.