Platelet-derived growth factor (PDGF), a potent chemotactic and mitogenic factor, is involved in the regulation of hematopoiesis and platelet production. Our studies demonstrate the presence of functional PDGF receptors (PDGFR) on human megakaryocytes/platelets and CD34(+) cells, and their ability to mediate a mitogenic response. PDGF promotes the ex vivo expansion of human hematopoietic stem (CD34(+)) and progenitor (CD41(+)) cells. More significantly, PDGF enhances the engraftment of human CD45(+) cells and their myeloid subsets (CD33(+), CD14(+) cells) in NOD/SCID mice. PDGF also stimulates in vitro megakaryocytopoiesis via PDGFR and/or the indirect effect on bone marrow microenvironment to produce TPO and other cytokines. It also shows a direct stimulatory effect of PDGF on c-Fos, GATA-1 and NF-E2 expressions in megakaryocytes. We speculate that these transcription factors may be involved in the signal transduction of PDGF on the regulation of megakaryocytopoiesis. PDGF also enhances platelet recovery in mouse model with radiation-induced thrombocytopenia. This radioprotective effect is likely to be mediated via PDGFR with subsequent activation of the PI3K/Akt pathway. It provides a possible explanation that blockage of PDGFR may reduce thrombopoiesis and play a role in imatinib mesylate-induced thrombocytopenia.