OBJECTIVE To review current knowledge about cell-free hemoglobin solutions. METHODS A computerized MEDLINE search was used to retrieve all studies concerning cell-free hemoglobin solutions from 1990 to 2003. The reference lists of all available review articles and primary studies were also reviewed to identify references not identified in the computerized search. METHODS All clinical and experimental studies involving cell-free hemoglobin solutions were included. METHODS From the selected studies, information was obtained regarding the experimental model or the study population in which cell-free hemoglobin solutions were investigated, the type of cell-free hemoglobin solution used, their deleterious or beneficial effects, and their possible indications. RESULTS In many studies, hemoglobin solutions were considered as efficient resuscitative agents and good alternatives to red blood cell transfusion, owing to their marked vasopressor effect, coupled with their capacity to improve the microcirculation and rapidly restore metabolic parameters. The main problems identified include excessive systemic vasoconstriction and oxidative damage. Initial enthusiasm in the development of hemoglobin solutions has been tempered recently by the negative results of a U.S. multicenter trial studying the early infusion of diaspirin cross-linked hemoglobin in trauma patients. Nevertheless, the properties of diaspirin cross-linked hemoglobin (and particularly the strong vasopressor effects) cannot be attributed to all hemoglobin solutions, and results of new clinical studies are eagerly awaited to evaluate the potential benefit of such solutions in the management of trauma patients. CONCLUSIONS Today, we are aware of the effects of the first generation of blood substitutes. Further research is ongoing into newer solutions. One area of interest is the development of new molecular structures to decrease nitric oxide binding, thus minimizing any adverse events and maximizing potential benefits. Nevertheless, possible adverse effects need to be carefully evaluated before these agents can be widely administered.