The term thrombopoietin (TPO) was first coined in 1958 and used to describe the humoral substance responsible for causing the platelet count to rise in response to thrombocytopenic stimuli. Despite much progress during the 1980s in the purification and characterization of the humoral regulators of lymphocyte, erythrocyte, monocyte and granulocyte production, the successful search to purify and molecularly clone thrombopoietin did not begin until the oncogene v-mpl was discovered in 1990. Since that time the proto-oncogene c-mpl was identified and, based on homology arguments, believed to encode a hematopoietic cytokine receptor, a hypothesis later proven when the cytoplasmic domain was linked to the ligand binding domain of the IL-4 receptor and shown to support the IL-4 induced growth of hematopoietic cells (Skoda et al., 1993). Finally, two different strategies using c-mpl lead to the identification of a novel ligand for the receptor in 1994 (de Sauvage et al., 1994; Lok et al., 1994; Bartley et al., 1994), a protein that displays all the biologic properties of TPO. This review attempts to distill what has been learned of the molecular and cellular biology of TPO and its receptor during the past several years, and links this information to several new insights into human disease and its treatment.