High-dose chemotherapy followed by a peripheral blood stem cell transplant is successfully used for a wide variety of malignancies. A major drawback, however, is the delay in platelet recovery. Several clinical strategies using thrombopoietin (Tpo) have been developed in an attempt to speed up platelet repopulation. In contrast to its success in immune thrombocytopenia and in low-dose toxic chemotherapeutic regimens, Tpo appears less effective in the case of high-dose chemotherapy and peripheral blood stem cell transplant. To develop a successful therapeutic approach, more knowledge is needed on several aspects of megakaryocyte (progenitor) biology, such as homing to the bone marrow, endomitosis, and platelet formation. Interactions of the megakaryocytes with the marrow vasculature and the microvascular microenvironment are other key factors for optimal thrombocytopoiesis. The present report reviews the background of the inefficiency of Tpo after intensive chemotherapy and describes possible strategies that might lead to successful therapies to treat chemotherapy-induced thrombocytopenia.