Thrombocytosis is due to (a) a variety of disorders that cause reactive stimulation of platelet production, (b) familial mutations, or (c) essential thrombocythemia (ET) and other myeloproliferative disorders (MPDs). The MPDs are clonal abnormalities of the pluripotent hematopoietic stem cell. Dysregulation of megakaryocytopoiesis in ET involves defective binding of thrombopoietin by platelets and megakaryocytes resulting in increased levels of plasma free thrombopoietin, and increased sensitivity of megakaryocytes to thrombopoietin leading to their increased proliferation. Bleeding and thrombosis are the major causes of morbidity and mortality in ET and the other MPDs. The elevated platelet count and qualitative platelet defects have been implicated in the pathophysiology of these hemostatic problems. However, these platelet abnormalities do not correlate well with clinical complications. It is proposed that bleeding and thrombosis could be due to vascular abnormalities that result from dysfunctional hematopoietic stem cell-derived endothelial cells.