Blood transfusions are now an essential part of modern medicine. Transfusable red blood cells (RBCs) are employed in various therapeutic strategies; however, the processes of blood donation, collection, and administration still involve many limitations. Notably, a lack of donors, the risk of transfusion–transmitted disease, and recent pandemics such as COVID-19 have prompted us to search for alternative therapeutics to replace this resource. Originally, RBC production was attempted via the ex vivo differentiation of stem cells. However, a more approachable and effective cell source is now required for broader applications. As a viable alternative, pluripotent stem cells have been actively used in recent research. In this review, we discuss the basic concepts related to erythropoiesis, as well as early research using hematopoietic stem cells ex vivo, and discuss the current trend of in vitro erythropoiesis using human-induced pluripotent stem cells.