Summary. Thrombopoietin (TPO) is an essential hematopoietic cytokine for megakaryopoiesis. In 2002, we demonstrated that pegylated-recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increased platelet counts in patients with chronic immune thrombocytopenic purpura (ITP) in a Phase I/II clinical trial. After the cessation of clinical trials of PEG-rHuMGDF because of severe thrombocytopenia or pancytopenia due to the development of the neutralizing antibody cross-reacting with endogenous TPO, second generation non-immunogenic TPO receptor agonists have been developed. A small molecule eltrombopag and Romiplostim were approved for clinical use by FDA in 2008 to treat patients with chronic ITP who are refractory to the prior therapy. Although the efficacy of both TPO receptor agonists is convincing for the refractory ITP, further investigation is necessary to assess the potential long-term side effects and clinical applications of these therapies for other thrombocytopenic conditions.