Most biomedical textbooks teach that coagulation and thrombosis are primarily a function of endothelial cells, platelets, and soluble coagulation factors. Red blood cells, in contrast, are generally regarded as innocent bystanders, passively entrapped in a developing thrombus as they flow through the vasculature. This review summarizes evidence that demonstrates an active role for red cells in normal and pathologic hemostasis. We then evaluate the possible molecular mechanisms whereby a usually inert erythrocyte can actively contribute to the processes of clot formation.