Thrombocytopenia is common among sick neonates, affecting 20% to 35% of all patients admitted to the neonatal intensive care unit (NICU). While most cases of neonatal thrombocytopenia are mild or moderate and resolve within 7 to 14 days with appropriate therapy, 2.5% to 5% of NICU patients develop severe thrombocytopenia, sometimes lasting for several weeks and requiring >20 platelet transfusions. The availability of thrombopoietic agents offers the possibility of decreasing the number of platelet transfusions and potentially improving the outcomes of these infants. However, adding thrombopoietin (TPO) mimetics to the therapeutic armamentarium of neonatologists will require careful attention to the substantial developmental differences between neonates and adults in the process of megakaryocytopoiesis and in their responses to TPO. Taken together, the available data suggest that TPO mimetics will stimulate platelet production in neonates, but might do so through different mechanisms and at different doses than those established for adults. In addition, the specific groups of thrombocytopenic neonates most likely to benefit from therapy with TPO mimetics need to be defined, and the potential nonhematological effects of these agents on the developing organism need to be considered. This review summarizes our current understanding of neonatal megakaryocytopoiesis, and examines in detail the developmental factors relevant to the potential use of TPO mimetics in neonates.