Prospects for safe and effective blood substitutes are promising, based on clinical trial results of soluble hemoglobin solutions and emulsion of perfluorocarbins. Advantages of blood substitutes include sterilization of viral and bacterial contaminants, room temperature storage, a long shelf life, and absence of ABO and other red cell antigens. Projected arenas for their use include not only military applications but also trauma medicine and elective surgical settings, coupled with acute normovolemic hemodilution. Applications of perfluorocarbons are limited by the need for 100% FIO2. A significant challenge facing development of hemoglobin solutions is their effect on vascular tone through smooth muscle constriction. Development of second or third generation hemoglobin solutions may be necessary so that hemoglobin solutions more closely mimic cellular hemoglobin's nitric oxide binding properties. Optimizing O2 delivery to ischemic tissues and organs may lead to regulatory approval of these agents in this setting before their approval as blood substitutes.