Erythropoiesis is regulated by a number of growth factors, among which stem cell factor (SCF) and erythropoietin (Epo) play a non-redundant function. Viable mice with mutations in the SCF gene (encoded by the Steel (Sl) locus), or its receptor gene c-Kit (encoded by the White spotting (W) locus) develop a hypoplastic macrocytic anemia. Mutants of W or Sl that are completely devoid of c-Kit or SCF expression die in utero of anemia between days 14 and 16 of gestation and contain reduced numbers of erythroid progenitors in the fetal liver. Likewise, Epo and Epo receptor (Epo-R)-deficient mice die in utero due to a marked reduction in the number of committed fetal liver derived erythroid progenitors. Thus, committed erythroid progenitors require both c-Kit and Epo-R signal transduction pathways for their survival, proliferation and differentiation. In vitro, Epo alone is capable of generating mature erythroid progenitors; however, a combined treatment of Epo and SCF results in synergistic proliferation and expansion of developing erythroid progenitors. This review summarizes recent advances made towards understanding the signaling mechanisms by which Epo-R and c-Kit regulate growth, survival, and differentiation of erythroid progenitors alone and cooperatively.