Concerns about blood safety and the logistical problems associated with conventional transfusion have fuelled the search for effective alternatives (so-called blood substitutes). Such materials include hemoglobin derivatives and those based on synthetic, highly fluorinated, inert organic compounds called perfluorochemicals (PFCs). PFCs dissolve large volumes of oxygen and other gases, are unreactive in the body, and are excreted primarily as a vapor by exhalation. Liquid PFCs are immiscible with blood and other body fluids, but can be injected safely into the bloodstream as submicron emulsions. Emulsified PFCs have been evaluated in clinical trials as temporary, intravascular tissue-oxygenating fluids. One such emulsion, a commercial perflubron-based, phospholipid-stabilized formulation, is in advanced clinical trials as an alternative to transfusing donated (allogeneic) blood during surgery. Basic and clinical studies have shown that this emulsion can adequately maintain tissue oxygenation during acute blood loss with no abnormal hemodynamic changes. The use of PFC emulsions as an efficacious, short-term transfusion alternative underpins the longer term objective of producing a totally synthetic, bioengineered blood substitute.