In hematopoietic stem cells and megakaryocytes, the thrombopoietin (TPO) receptor signals to control proliferation, maturation, and antiapoptosis. In the anucleated platelet, much of this signaling appears out of place. Nevertheless, platelets possess TPO receptors and the cascades for transduction of TPO signals, but the final effect has shifted from DNA regulation to control of platelet aggregation and secretion. Although at physiological concentrations, TPO is not a sufficiently strong stimulator to trigger platelet functions in the absence of a second stimulator, TPO increases the sensitivity of platelets to agonist stimulation, leading to better functions at lower stimulation.