In contrast to an obsolete notion that erythrocytes, or red blood cells (RBCs), play a passive and minor role in hemostasis and thrombosis, over the past decades there has been increasing evidence that RBCs have biologically and clinically important functions in blood clotting and its disorders. This review summarizes the main mechanisms that underlie the involvement of RBCs in hemostasis and thrombosis in vivo, such as rheological effects on blood viscosity and platelet margination, aggregation and deformability of RBCs; direct adhesion and indirect biochemical interactions with endothelial cells and platelets, etc. The ability of stored and pathologically altered RBCs to generate thrombin through exposure of phosphatidylserine has been emphasized. The procoagulant and prothrombotic potential of RBC-derived microparticles transfused with stored RBCs or formed in various pathological conditions associated with hemolysis has been described along with prothrombotic effects of free hemoglobin and heme. Binding of fibrinogen or fibrin to RBCs may influence their effects on fibrin network structure, clot mechanical properties, and fibrinolytic resistance. Recent data on platelet-driven clot contraction show that RBCs compressed by platelets pulling on fibrin form a tightly packed array of polyhedral erythrocytes, or polyhedrocytes, which comprises a nearly impermeable barrier important for hemostasis and wound healing. RBCs may perform dual roles, both helping to stem bleeding but at the same time contributing to thrombosis in a variety of ways.