For almost a century, scientists have been pursuing the development of “artificial blood” — seeking a product that would be safe, universally compatible with all blood types, and readily available. The commercial development of hemoglobin (Hb) and perfluorochemical (PFC) based oxygen carriers over the past 30 years has followed a rather complex pathway characterized by early promises, safety concerns, frequent setbacks, and the potential for major commercial success. Along the way, however, various preclinical efficacy studies have revealed that these products are truly oxygen therapeutics and that they may be more than just temporary “blood substitutes”. While they clearly have the potential to radically alter blood transfusion practice, their ability to deliver oxygen to tissues in ways that differ from and are more efficient than red blood cells make them attractive drugs for use in a variety of clinical situations and medical conditions where vital tissues are at risk of acute hypoxia.