Abstract Platelet-derived growth factor-BB (PDGF-BB) is a well-characterized growth factor displaying potent biological effects on angiogenesis. Recent studies reveal that overexpression of PDGF-BB within tumors results in increased pericyte coverage, suggesting that PDGF-BB signaling is also essential for the cancerous pericyte recruitment process. However, the molecular mechanism underlying this regulation remains obscure. In the current study, we show that tumor-derived PDGF-BB induces SDF-1α expression in endothelial cells (EC), resulting in the formation of SDF-1α chemotaxis gradient, which coincides with the PDGF-BB–induced pericyte recruitment during angiogenesis. PDGF-BB dramatically up-regulates SDF-1α secretion through the activation of PDGFRβ in tumor-associated ECs, whereas this up-regulation can be substantially inhibited by either blockade of the phosphatidylinositol 3-kinase/Akt/mTOR pathway with chemical inhibitors or the inactivation of HIF-1α through small interfering RNA interference. On the other hand, we reveal that SDF-1α can increase pericytes motility in vitro. Blockade of the SDF-1α/CXCR4 axis prevents the PDGF-BB–induced pericyte recruitment not only in three in vitro recruitment models but also in the PDGF-BB–overexpressing tumor xenograft models. These results highlight that the involvement of SDF-1α/CXCR4 axis is essential for the pericyte recruitment within the PDGF-BB–overexpressing tumors and raise the possibility that blockade of the SDF-1α/CXCR4 axis may provide a therapeutic synergy with antiangiogenic molecules that selectively target ECs. [Cancer Res 2009;69(15):6057–64]