Thrombopoietin (TPO) is a cytokine that is involved in the regulation of platelet production. The receptor for TPO is c-Mpl. To further investigate the role and specificity of this receptor in regulating megakaryocytopoiesis, c-mpl-deficient mice were generated by gene targeting. The c-mpl(-/-) mice had an 85 percent decrease in their number of platelets and megakaryocytes but had normal amounts of other hematopoietic cell types. These mice also had increased concentrations of circulating TPO. These results show that c-mpl specifically regulates megakaryocytopoiesis and thrombopoiesis through activation by its ligand TPO.