Mpl, the receptor for thrombopoietin (TPO), was isolated as a cellular sequence transduced by a new acute myeloproliferative virus. Human and murine c-mpl were subsequently cloned and Mpl was identified as a member of the growth factor receptor superfamily. For a time, Mpl remained an orphan receptor. Engineering of cell lines expressing c-mpl provided a sensitive tool for detecting the ligand of Mpl, and led to the molecular cloning of TPO, the long sought proliferation and differentiation factor for the megakaryocytic lineage. Afterwards, signal transduction by Mpl was studied, and the functional elements of the cytoplasmic domain responsible for cell proliferation and differentiation were identified. When studied in various human hematologic malignancies, Mpl expression was shown to be increased in 50% of the patients with acute myeloblastic leukemia (AML). In vitro treatment of AML cells by TPO led to proliferation, suggesting that TPO could contribute, at least in part, to abnormal growth of AML cells. A tremendous number of studies have followed the isolation of TPO, and have shown that TPO is the primary regulator of physiological platelet production. However, roles for Mpl and TPO in other lineages, especially in erythroid and immature hematopoietic progenitors, have also emerged from these studies.