Thrombocytopenia that results from chemotherapy has become an increasingly important issue in the treatment of cancer and remains a difficult clinical problem. The identification of a safe and effective platelet growth factor could significantly improve the management of severe chemotherapy-induced thrombocytopenia. Over the past decade, a number of hematopoietic growth factors with thrombopoietic activity have been identified, including stem-cell factor (c-kit ligand), interleukin (IL)-1, IL-3, IL-6, and IL-11, as well as thrombopoietin (TPO) and its derivatives. Only a few of these agents have shown acceptable tolerability and sufficient ability to stimulate thrombopoiesis to justify testing in randomized clinical trials. Currently, IL-11 is the only cytokine licensed in the United States for treatment of chemotherapy-induced thrombocytopenia. However, its thrombopoietic activity is modest and its use is often associated with unfavorable side effects. Identification of TPO, the c-Mpl ligand, as the primary physiologic regulator of megakaryocyte and platelet development offers important promise for treatment of thrombocytopenia. Preliminary clinical studies of recombinant human TPO (rhTPO), a full-length glycosylated molecule, indicate that it is safe and biologically active in reducing severe chemotherapy-induced thrombocytopenia. In addition to rhTPO, the future may see the development of novel genetically engineered, high-affinity cytokine receptor agonists and c-Mpl ligand mimetic peptides.