Three types of materials have been studied as candidate blood substitutes: the perfluorocarbons, modified hemoglobins, and liposome-encapsulated hemoglobin. Progress has been greatest with the hemoglobin-based oxygen carriers. Hemoglobin is a highly active molecule; hence, modification has been required to avoid potential deleterious effects. Although there has been considerable progress toward bringing such a product to the clinic, its development has challenged understanding of oxygen delivery and use. The study of these molecules has provided new insights into basic physiologic processes.