Thrombocytopenia, common in leukemias and myelodysplastic syndromes (MDS), is responsible for increased risk of bleeding and delay of therapy. Platelet transfusions, although effective in increasing platelet counts, are limited by supply, are associated with risks, and result in limited and transient benefits. Successful development of an alternative treatment approach with thrombopoietin agonists was nearly thwarted when early formulations of recombinant thrombopoietin agonists elicited antibodies that cross-reacted with and neutralized endogenous thrombopoietin. The effectiveness of these recombinant agents led to the development of second-generation thrombopoietin receptor agonists that do not induce cross-reacting neutralizing antibodies against thrombopoietin. Two of the novel thrombopoietin receptor agonists, romiplostim and eltrombopag, have established clinical activity in chronic immune (idiopathic) thrombocytopenic purpura (ITP), and are being explored for the treatment of thrombocytopenia in MDS.