The story of the developmental changes in erythropoiesis is the history of oxygenation in the developing organism. The individual components of the switch from embryonic to adult erythropoiesis are developmentally regulated, and their interaction with one another is complex. Basic defects, such as absence of Epo production, lead to early embryonic or fetal death. Other defects, such as abnormalities in the switch from the fetal to adult erythropoiesis, are less catastrophic but result in hematologic abnormalities. Understanding the many aspects of the switch from embryonic to fetal to adult erythropoiesis can lead to an improved awareness of many of the problems typical of preterm infants, inborn errors resulting in hematologic diseases, and aspects important for transplantation medicine.