A LTHOUGH THE CONCEPT was advanced some 37 years ago, evidence for the existence of a humoral regulator of platelet production, first termed thrombopoietin (Tpo) by Kelemen et al,'accumulated very slowly. Initial studies in the 1960s and 1970s indicated that thrombocytopenia evokes characteristic marrow changes including increases in the number, size, ploidy, and maturation rate of megakaryocyte^.^" Platelet transfusion-induced thrombocytosis was associated with the opposite effects.* These findings were later confirmed with the availability of improved methods of assessing cellular DNA content and megakaryocyte maturation.'"'Ode11 et allz are generally acknowledged as providing the first description of a humoral substance in the sera of thrombocytopenic rats which induced thrombocytosis in recipient animals. Subsequent investigators have reported that thrombocytopenic serum also induces many of the marrow effects associated with thromb~ cytopenia.'~"~ However, significant progress in the field awaited the development of reliable, albeit cumbersome, assays of Tpo activity. I7-*'Attempts to biochemically purify Tpo from plasma, serum, urine, and conditioned culture medium from various cell lines occupied much effort during the 1 9 8 0~.~"~~ Unfortunately, because of the complex nature of the starting material and difficulties associated with the use of an in vivo assay, these attempts failed to yield homogeneous protein adequate for protein sequencing and cDNA cloning, the official rite of passage for a hematopoietic growth factor. Furthermore, a number of cytokines were described in the late 1980s and early 1990s that possessed activity in various assays of megakaryocyte development. 2943 During the past several years, many investigators suggested that a distinct, lineage-specific thrombopoietin may not exist.