Now a routine lifesaving treatment, blood transfusion between humans became a safe procedure only after many early therapeutic disasters. Performed between different species, heterologous transfusions actually succeeded homologous transfusions, those performed between members of the same species. In the early history of transfusion, both homologous and heterologous transfusions were performed in many clinical settings. Early clinicians were unable to distinguish between deaths caused by baseline illness and those resulting from transfusions. This report examines both early experiments with homologous transfusion between animals and later efforts investigating and finally abandoning heterologous transfusion. Topics explored include: 1) contributions and lessons learned from key individuals, 2) how these researchers suggested, performed, advocated, or challenged the practice of heterologous transfusion, and 3) why heterologous transfusions were even considered as a mode of therapy.