The transfusion of animal blood or red blood cells (RBCs) into humans goes back to 1667, and the practice persisted until the early 1900s. In recent years, in part because of the shortage of acceptable and safe human blood worldwide, there has been renewed interest in the possibility of using genetically-engineered pigs as sources of RBCs for clinical transfusion. Pigs are becoming available in which the cells, tissues, and organs are to some extent protected from the human immune response. This extends significant protection from antibody-mediated complement lysis. Transfusion of these RBCs into nonhuman primates, however, indicates that they are rapidly lost from the circulation, almost certainly through the phagocytic activity of macrophages. Further genetic manipulation may resolve this problem. In view of the potential advantages of pig RBCs with regard to the absence of infectious microorganisms and the rapid progress being made in genetically modifying pigs, pig RBCs may eventually become a feasible source of blood for clinical transfusion.