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Abstract: One has been trying for several years to find a substitute for red blood cells (RBC). The development of chemical or natural molecules to replace hemoglobin has nevertheless proved difficult and artificial blood is still unattainable. We have described a methodology permitting the massive ex vivo production of mature human RBC having all the characteristics of native adult RBC from hematopoietic stem cells (HSC) of diverse origins: blood, bone marrow or cord blood. This protocol allows both massive expansion of the HSC/progenitors and their complete differentiation to the stage of perfectly functional mature RBC. The levels of amplification obtained (105 to 2×105) are compatible with an eventual transfusion application. We discuss here the state of the art of this new concept and evoke the obstacles to be overcome to pass from the laboratory model to clinical practice. This concept of “cultured RBC” opens up potentially considerable therapeutic perspectives in the field of blood transfusion. [Copyright &y& Elsevier]