Three polyhemoglobins, formed by intermolecular cross-linking of hemoglobin molecules are in advanced phase III clinical trials and two conjugated hemoglobins, formed by cross-linking of hemoglobin molecules with soluble polymer, are also undergoing clinical trials. A perflubron-based emulsion is undergoing phase III clinical trials and a new recombinant human hemoglobin that does not bind to nitric oxide is also being developed. New oxygen carriers with antioxidant properties are being developed for conditions with potential for ischemia-reperfusion injuries. Third generation oxygen carriers are based on microencapsulation of hemoglobin and red blood cell enzymes either in liposomes or in biodegradable nanocapsules. This review will briefly discuss lessons learnt from the past, give an overview on the current status of selected oxygen carriers and discuss research areas in need of further development.