The sickle red blood cell (SS RBC) as source of multiple pathophysiologic pathways. Red cells with predominantly HbS (SS RBCs) become rapidly dehydrated, which increases the propensity of HbS to polymerize when deoxygenated. Pharmacologic reagents that prevent dehydration may therefore also reduce HbS polymerization and hemolysis. Altered lipid sidedness (phosphatidylserine exposure) may play a role in SS RBC adhesion and also promote activation of coagulation. Oxidative damage of red cell membrane proteins likely contributes to altered cell elasticity. Abnormal adhesive properties lead to SS RBC adhesion to endothelial cells (A), SS RBC adhesion to neutrophils (B), and adhesive interactions that result in heterocellular aggregate formation involving SS RBCs, monocytes, and platelets (C). Abnormal intracellular signaling increases the activation state of red cell adhesion molecules, and increased adhesive interactions then lead to abnormally active cell-cell signaling, which leads to activation of both other blood cells and endothelial cells. Both SS RBCs and hypoxia/reperfusion also lead to activation of inflammatory pathways involving both mononuclear and polymorphonuclear leukocytes. Platelet activation also contributes to inflammatory pathways as well as activation of coagulation.