Homozygous natural white-spotted (W) mutations in the gene encoding the receptor tyrosine kinase c-Kit are associated with hypoplastic bone marrow, severe macrocytic anemia, and lethality during early postnatal life. c-Kit^W/W mice can be rescued by wild-type hematopoietic stem cells (HSCs), but it is not known whether the lethality of c-Kit^W/W mice is the result of HSC failure or defects specific for erythropoiesis. Here we show that transgenic expression of erythropoietin (EPO) can overcome the lethality caused by the c-Kit^W/W mutation. In W mutant mice rescued by EPO, termed WEPO, erythrocyte colony-forming units (CFU-Es) are rescued to normal frequencies. Hence, Epo receptor signals can partially bypass the strict requirement for c-Kit signaling in erythropoiesis in the absence of c-Kit in vivo. Using a series of W and rescue mouse strains, we define here the erythropoietic threshold permitting survival in vivo. The lethality of c-Kit^W/W mice has precluded analysis of this crucial receptor-ligand pair in adult stem/progenitor cells. Our strategy to generate viable c-Kit^W/W mice will be useful to analyze the role of this important receptor tyrosine kinase in adult life in vivo. (Blood. 2004; 104:1688-1695)