Erythropoietin (Epo) and its receptor (EpoR) are essential for proliferation, differentiation and survival of erythroid progenitors. Here, we review several mechanisms by which the EpoR can be activated. We also describe the many intracellular signal transduction pathways activated by the EpoR. None are unique to the EpoR and mutant receptors able to activate only a subset of these pathways can support erythropoiesis in EpoR-/- fetal liver cells. Furthermore, normal erythroid differentiation occurs when the EpoR is replaced by the prolactin receptor or the myeloid oncoprotein Bcr-abl. Epo and probably other growth factors are required merely to ensure the survival and proliferation of already committed progenitors.