Jak inhibitors have recently attracted considerable attention as new drugs for the treatment of autoimmune diseases and myeofibrosis, but often give rise to anemia as an adverse effect. To understand the mechanism underlying Jak-Stat activation in the erythropoiesis is needed for the therapeutic intervention into such anemic conditions. Calcium ion (Ca2+) acts as a major second messenger responsible for a variety of intracellular signaling pathways. Proteins with the EF hand motif, a common Ca2+-binding motif, are important for the intracellular Ca2+ signal. A number of proteins with EF hand motif that mediate the biological effects of Ca2+ have been identified so far, but the physiological roles of some of them remain largely unknown. Here we identified an EF-hand motif protein (hereafter called Efp) as a new regulator for Jak-Stat signaling pathway. Since Efp is expressed at high level in hematopoietic cell lineage, we newly generated the Efp floxed mice and analyzed the hematopoietic lineage-specific Efp-deficient mice by mating them with Vav-iCre transgenic mice. Hematopoietic lineage-specific Efp-deficient mice were born with a pale skin at the expected Mendelian ratio and die soon after birth because of severe anemia. Blood test using the peripheral blood revealed a decrease in the number of red blood cells and low hemoglobin in hematopoietic lineage-specific Efp-deficient mice. On the other hand, these neonatal mice exhibited normal number of CD11b+ myeloid cells, CD3+ T cells and B220+ B cells. Activation of Jak-Stat pathway by erythropoietin was inhibited in the Efp-deficient fetal liver cells, whereas IL-3 or GM-CSF-induced Jak activation was normally activated. These results indicate that Efp regulates the Jak-Stat signaling pathway downstream of certain types of cytokines. We will also discuss roles of Efp in lymphocyte development by analyzing the lymphocyte-specific conditional knockout mice.