Alternative oxygen carriers are being evaluated in human studies. Information from the clinical evaluation of these "blood substitutes" is not publicly available. Preclinical studies of solutions of modified cell-free hemoglobin and of perfluorocarbon emulsions have demonstrated significant toxicity. Hemoglobin inactivates endothelium-derived nitric oxide, participates in free-radical reactions, is a neurotoxin, activates the immune system, potentiates the effects of bacterial endotoxin, and increases the lethality of certain bacterial infections. Perfluorocarbon emulsions activate complement and cause lung dysfunction. Both materials have short intravascular half-lives. Safe doses of perfluorocarbon emulsions have very limited oxygen-carrying capacity. Protein engineering to reduce the toxicities of the modified hemoglobins is ongoing. A safe and effective erythrocyte substitute is still a distant goal.