Daily injections of 60 µg. actinomycin D per Kg. mouse caused cessation of erythropoiesis due to complete disappearance of erythroid marrow elements, and the mice were absolutely refractory to erythropoietin. No decrease in myelo-, lympho-, or megakaryocytopoiesis was found during more than 3 weeks of daily administration of the drug. Observations on the effect of the drug on a cohort of erythroid cells, induced by erythropoietin in polycythemic mice, gave no evidence of its destructive or inhibitory action on early or late normoblasts. A critical reduction in the number of integer stem cells was likewise ruled out as the cause of eradication of erythropoiesis. The latter is attributed to a specific interference of actinomycin D in the effector pathway of erythropoietin controlled transformation (differentiation) of stem cells into early pronormoblasts. The findings indicate this process to be contingent on formation of new types of mRNA rather than on activation of templates already present in erythropoietin-sensitive stem cells.