Several complications and unforeseen adverse side effects have colluded to keep commercially available blood substitutes or oxygen therapeutic agents tantalizingly "just out of reach." Because the three classes of agents under development have different oxygen-delivery mechanisms and side-effect profiles, each can be expected to have its own unique clinical applications, particularly in the cardiac surgery population. The fact that South Africa recently approved one HBOC for use as a transfusion alternative in patients with chronic anemia indicates that initial clinical use is near for a number of these agents. It is to be hoped that they will be used for several applications rather than just for a "transfusion alternative." Despite some frustrating limitations, all of these agents are antigen and pathogen free, have an acceptable side-effect profile, and have a long shelf life. Increasing volunteer-blood-donor shortages, coupled with increasing blood-transfusion needs, and expanding human immunodeficiency virus and hepatitis B and C epidemics, continue to fuel the demand for further development of these products. Transfusion alternatives will eventually become commercially available - the question is "when," not "if." Equally important, these agents' potential for serving as effective oxygen-delivery agents to ischemic tissues heralds an entirely new field of clinical investigation.