Thrombopoietin (TPO) is the physiologic regulator of platelet production and works by binding to its receptor on megakaryocyte precursor cells, thereby activating a large number of antiapoptotic and cell maturation pathways. "First-generation" recombinant forms of TPO were developed over a decade ago and were found to increase the platelet count in patients undergoing nonmyeloablative chemotherapy, in patients with immune thrombocytopenic purpura (ITP) and myelodysplasia, as well as in platelet apheresis donors. Thrombopoietin did not improve platelet counts in patients undergoing stem cell transplantation or acute leukemia induction. Further development ended when antibodies formed against one of the recombinant proteins. Subsequently, 2 "second-generation" TPO mimetics have been developed and are entering clinical practice: romiplostim and eltrombopag. Romiplostim is an injectable peptide TPO mimetic that activates the TPO receptor just like native TPO. Eltrombopag is an oral nonpeptide TPO mimetic that activates the TPO receptor by binding to a different region of the TPO receptor that does not compete with TPO binding. Both increased the platelet counts in healthy subjects and in over two thirds of patients with ITP both before and after splenectomy; responses were maintained for at least 1 year. Romiplostim and eltrombopag are now US Food and Drug Administration approved for the second-line treatment of patients with ITP. Adverse events have been few, but long-term assessment for reticulin formation, increased bone marrow blasts, and thromboembolism is ongoing. Studies are under way to assess the efficacy of these drugs in the treatment of other thrombocytopenic disorders associated with chemotherapy, myelodysplasia, and chronic hepatitis.