Thrombopoietin (Tpo), the ligand for the receptor encoded by the c-Mpl proto-oncogene, is a key regulator of megakaryocytopoiesis and thrombopoiesis in vitro and in vivo. The cDNAs for Tpo have recently been cloned from canine, murine and human sources. The proteins from these three species are highly conserved, exhibiting from 69-75% sequence identity at the amino acid level. Human Tpo cDNA encodes a 353 amino acid residue protein with a 21 amino acid residue signal peptide that is cleaved to yield the 332 amino acid residue mature protein. Two distinct domains, separated by a pair of arginine residues that may be a proteolytic cleavage site, have been identified in Tpo: the amino terminal region exhibiting sequence homology to erythropoietin and the carboxy terminal region containing multiple potential N-linked glycosylation sites. Recombinant Tpo has now been shown to stimulate the maturation, as well as the proliferation, of megakaryocytes and may have important therapeutic applications for the treatment of various clinical conditions associated with thrombocytopenia.