Lyn kinase is known to modulate the formation and function of B cells, monocytes, and mast cells. However, Lyn-/- mice also develop erythrosplenomegaly, and cases for both negative and positive erythropoietic actions of Lyn recently have been outlined. In phenylhydrazine-treated Lyn-/- mice, extramedullary splenic erythropoiesis was hyperactivated, but this did not lead to accelerated recovery from anemia. Furthermore, ex vivo analyses of the development of bone marrow-derived Lyn-/- erythroblasts in unique primary culture systems indicated positive roles for Lyn at 2 stages. Late-stage Lyn-/- erythroblasts exhibited deficit Ter119(pos) cell formation, and this was paralleled by increased apoptosis (and decreased Bcl-xL expression). During early development, Lyn-/- erythroblasts accumulated at a Kit(pos)CD71(high) stage, possessed decreased proliferative capacity, and were attenuated in entering an apparent G1/S cell-cycle phase. In proposed compensatory responses, Lyn-/- erythroblasts expressed increased levels of activated Akt and p60-Src and decreased levels of death-associated protein kinase-2. Stat5 activation and Bcl-xL expression, in contrast, were significantly decreased in keeping with decreased survival and developmental potentials. Lyn, therefore, is proposed to function via erythroid cell-intrinsic mechanisms to promote progenitor cell expansion beyond a Kit(pos)CD71(high) stage and to support subsequent late-stage development.