Following a prolonged gestation, thrombopoietin was cloned in 1994 and now commands center stage as the preeminent growth factor affecting megakaryopoiesis. In this chapter, following a brief introduction to the megakaryocytic lineage, the history and discovery of thrombopoietin is described. Building on this background, a detailed account of the biochemistry, molecular biology and genetics of thrombopoietin and its receptor c-mpl is presented. Although available for only a short time, this recombinant protein has facilitated many new insights concerning the biology of platelet production and homeostasis. Furthermore, thrombopoietin has been applied in the clinical context of high dose chemoradiotherapy and bone marrow transplantation. The current phase of thrombopoietin’s clinical development represents an exciting culmination of intense basic research and a promising début for future therapies.