Blood transfusion is an indispensable cell therapy. Red blood cell (RBC) transfusion depends on the availability of donor material, and concerns over supply and safety have spurred development of methods to manufacture blood from stem cells. Recent advances have increased excitement about the potential therapeutic production of RBCs ex vivo. Current methods could theoretically yield therapeutic doses of RBCs. However, generation of RBCs in the large numbers required for transfusion remains a significant challenge. In this article, we review the recent progress made in producing RBCs from various cell sources for transfusion purposes and discuss the most compelling issues to be addressed to translate this progress into a clinical-grade transfusion product. It is hoped that ongoing efforts and new technologies for ex vivo erythrocytes generation will provide alternative transfusion products to meet present and future clinical requirements.