In summary, we have shown that clonogenic precursors of both primitive and definitive erythroblasts can be isolated from early stage mouse conceptuses and stimulated to form colonies in standard methylcellulose cultures containing Ep and SCCM. These two types of precursors appear to differ not only in their ability to produce HbE-synthesizing progeny, but also in their innate sensitivity to physical or enzymatic treatment, and in their maturation kinetics and differential responsiveness to SCCM. On the basis of sequential studies of the distribution of these precursors in the yolk sac, early circulation and fetal liver it appears most likely that in the mouse, both primitive and definitive hemopoietic cells originate extra-embryonically in the yolk sac blood islands. We suggest that commitment to primitive erythropoiesis is an early transient event that leads to the rapid and exclusive production of primitive erythroblasts. All other cells become committed to definitive erythropoiesis and this decision may precede actual restriction of differentiation potential to the erythroid lineage. As a result only definitive pluripotent stem cells enter the circulation and hence seed the other hemopoietic tissues.