Thrombopoietin (TPO) is the central regulator of megakaryocytopoiesis and thrombocytopoiesis. Preclinical data and human studies have so far shown that the recombinant molecule is safe to administer and associated with very little toxicity. Nevertheless, different experimental animal models have revealed that a chronic exposure to very high doses of TPO could result in myeloproliferative syndromes with a spectrum of pathological features in common with human idiopathic myelofibrosis (PMF). A number of investigators have researched whether TPO or its receptor Mpl were involved in the pathogenesis of human myeloproliferative syndromes which are also characterized by a predominant megakaryocytic involvement, in PMF and primitive essential thrombocythemia. In both diseases, megakaryocyte (MK) progenitors develop autonomously in serum-deprived cultures. This spontaneous MK development is also observed at limiting dilution demonstrating that MK escape the normal regulatory controls. Furthermore, this abnormal MK proliferation and maturation is neither due to an autocrine stimulation by TPO nor by point mutation or deletion in the coding region of the c-mpl gene. This paper will review the data that have been reported to date on the effects of an overexpression of Mpl ligand and related molecules on the induction of experimental myelofibrosis and highlight recent insights into the pathogenesis of PMF.