Thrombopoietin (TPO) is a key physiological regulator of steady-state megakaryocytopoiesis, the process of megakaryocyte production and maturation that ultimately results in the formation of platelets. Ten years have passed since the purification and cloning of TPO and extensive studies of the activities of recombinant forms of the cytokine, as well as analyses of genetically modified mice lacking or over-expressing TPO or its receptor c-Mpl, have defined the role of TPO in megakaryocytopoiesis as well as uncovered unanticipated actions. Biochemical analyses have identified a number of signalling pathways, including the Jak/signal transducers and activators of transcription (STAT) and Ras cascades that transmit signals from the activated cell surface receptor complex to the cell nucleus resulting in changes in gene expression and the biological responses of TPO-stimulated cells. Since TPO is the most potent known stimulus of platelet production in vivo, the evaluation of this cytokine for clinical use in the treatment of thrombocytopenia is being actively pursued and recent studies have suggested that aberrations in the TPO signalling pathway may contribute to disease.