Early approaches to the development of oxygen carriers involved the use of stroma-free hemoglobin solutions. These solutions did not require blood typing or crossmatching and could be stored for long periods. In addition, a variety of methods have been developed in chemically modifying and stabilizing the hemoglobin molecule. Several hemoglobin therapeutics are now in clinical trials as temporary alternatives to blood or as therapeutic agents for ischemia. The various hemoglobin products under development are derived from three principal sources: human, bovine and genetically engineered hemoglobin. Diaspirin cross-linked hemoglobin (DCLHb), administered at doses ranging from approximately 20-1000 ml, has been investigated in a number of clinical trials in patients undergoing orthopedic, abdominal aortic repair, major abdominal surgery, cardiac surgery and in critically ill patients with septic shock. In several studies, DCLHb was effective in avoiding the transfusion. However, Baxter Healthcare Corporation (Chicago, Illinois, USA) stopped the development of DCLHb after two unsuccessful trials in trauma patients. Bovine polymerized hemoglobin has also been extensively studied. Several phase II and phase III trials have been performed with this product in hemorrhagic surgery, cardiac surgery and vascular surgery, but data have not yet been published. Hemoglobin therapeutics could provide an important new option as an alternative to blood transfusion. Furthermore, they may be able to provide an immediate on-site replacement for traumatic blood loss, prevent global ischemia and organ failure, treat focal ischemia, and provide effective hemodynamic support for septic shock-induced hypotension.