The thrombopoietin receptor, c-mpl, is a member of the hematopoietin/cytokine receptor superfamily and consists of two duplicated hematopoietin receptor domains (HRD). The proximal HRD is responsible for receptor dimerization and consequent signal transduction and the distal HRD may regulate its action. The thrombopoietin receptor is found on many hematopoietic progenitors but is primarily found on megakaryocytes and platelets. The platelet receptor is of high binding affinity (120-200pM) but low surface density (30-60 sites per cell). Receptor binding by thrombopoietin results in the promotion of cell growth/cellular differentiation, the prevention of apoptosis, and the internalization and degradation of the receptor-ligand complex. Loss of the distal HRD by fusion with the murine leukemia virus env protein results in unregulated expression of c-wpl and a myeloproliferative syndrome in mice. Mice deficient in the thrombopoietin receptor produce 10-15% as many megakaryocytes and platelets as wild-type mice but also have 25-35% the normal number of erythroid and myeloid progenitors despite normal peripheral red and white blood cell counts. No human abnormalities of c-mpl have yet been described and therapeutic use of the soluble receptor has not yet been demonstrated.