Thrombopoietin (TPO) is the key growth factor for physiologic megakaryopoiesis and is essential for platelet production [1–5]. TPO acts through its receptor, c-Mpl (member of the cytokine receptor superfamily), and the JAK-STAT signal transduction pathway [6,7]. The human TPO gene has been mapped to 3q27 [8] and that of c-Mpl to 1p34 [9]. In both human fetal and adult tissues, the highest TPO mRNA concentrations are found in the liver while a lesser degree of TPO expression is seen in the spleen, bone marrow (BM), and kidney [10–12]. Furthermore, local BM production of TPO may contribute to normal megakaryopoiesis as well as hemopoiesis in general [13–16]. Normal TPO production is constitutive [17] and circulating TPO is regulated by c-Mpl-mediated platelet binding, internalization, and catabolism [18–22]. As such, plasma TPO levels are, usually, inversely proportional to total megakaryocyte/platelet mass [23,24]. Accordingly, in hypomegakaryocytic thrombocytopenia including amegakaryocytic thrombocytopenia, aplastic anemia and chemotherapy-induced thrombocytopenia, there is marked elevation of serum TPO levels [25–28]. In contrast, in hypermegakaryocytic thrombocytopenia including immune thrombocytopenic purpura and post-transfusion purpura, the serum TPO levels are either not increased or only slightly increased [25–27]. The situation in thrombocythemic states is more complicated. Both reactive thrombocytosis (RT) and primary thrombocythemia associated with chronic myeloproliferative disorders (CMPD) are associated with either elevated or normal TPO levels despite the associated increase in megakaryocyte/platelet mass [29–33]. In case of RT, elevated plasma TPO level has been shown to antedate the increase in platelet count and is often associated with an increase in other megakaryopoietic cytokines that may contribute to increased hepatic production of TPO [34–37].