Megakaryopoiesis and thrombopoiesis are the central biological processes of platelet generation. Severe thrombocytopenia is a major morbidity and mortality factor in several diseases and represents a significant unmet medical need. Since the discovery of thrombopoietin (TPO) as the primary physiological regulator of megakaryopoiesis, a number of therapeutics have been developed for thrombocytopenia and been tested in preclinical models and human clinical trials. The TPO mimetics romiplostim (Nplate(®) or AMG531) and eltrombopag (Promacta(®)) have recently been approved for the treatment of adult chronic idiopathic (immune) thrombocytopenic purpura (ITP) and are successful examples of these endeavors. This chapter will review scientific progress over the last 20 years on various thrombopoietic factors with an emphasis on the biology, physiology, and pharmacology of TPO, its cognate receptor, c-Mpl, and various TPO mimetics.