Red blood cells play a key role in normal hemostasis and thrombosis. Their ability to affect coagulation is multifactorial and depends on their mechanical properties affecting viscosity and blood flow, ability to aggregate and adhere to each other and potentially to vascular endothelium, molecular signaling via microvesicles and surface proteins, including blood group antigens, and participation in nitric oxide metabolism. Transfused red blood cells suffer from a storage lesion that damages the cells leading to changes in shape, function, and intracellular communication. In this article, we review if and how transfused red blood cells may lead to both increased hemorrhage and increased thrombosis.