Thrombopoietin was posited to exist in 1958 and cloned in 1994, and in the ensuing two decades we have learned a great deal about the physiology and pathology of the primary regulator of thrombopoiesis. This paper will review the role of the hormone and its receptor, the product of the c-Mpl proto-oncogene, in health and disease, including many unexpected effects in both normal and neoplastic hematopoiesis. Amongst these unexpected properties are a non-redundant effect on hematopoietic stem cells, a critical role in all three of the acquired, chronic myeloproliferative neoplasms, as well as both gain-of-function and loss-of-function mutations in congenital and acquired states of thrombocytopenia and thrombocythemia.