Thrombopoietin (TPO) is the primary regulator of megakaryocyte (Meg) and platelet production. Its receptor, c-mpl, is a member of the cytokine receptor superfamily. Major insight into the physiological role of this receptor/ligand pair came from the study of mice carrying disrupted alleles of these two genes. Both TPO and c-mpl knockout mice are viable, but have a 90% reduction in platelet counts. Their thrombocytopenia is caused by a reduction in progenitor cell numbers and a decrease in Meg ploidy. However, the Megs and platelets produced in the absence of TPO or c-mpl appear morphologically and functionally normal indicating that, in vivo, the main role of TPO is to control their numbers, rather than their maturation. In addition to its effect on the Meg lineage, TPO also affects hematopoietic stem cells as measured by a reduction of the repopulating capacity of bone marrow cells from c-mpl-deficient mice. Finally, analysis of these gene targeted mice provided substantial evidence to a model where the circulating TPO level is directly regulated by the platelet mass through binding to c-mpl receptors present at the platelet surface. This elegant feedback mechanism allows a tight regulation of the amount of TPO available to stimulate megakaryocytopoiesis.