Umbilical cord blood-derived USSCs (unrestricted somatic stem cells) have recently been considered as a potential source for stem cell therapy and transplantation due to their characteristics such as easy accessibility, low immunogenicity, self-renewing and multilineage differentiation potential. Stem cell homing is a key factor in successful transplantation, which is regulated by CXCR4 in stem cells. In this study, we evaluated the expression of CXCR4 in USSCs different passages. Moreover, the effect of VEGF (vascular endothelial growth factor) and IGF-1 (insulin-like growth factor 1) on its expression was assessed. It was shown that the expression of CXCR4 in USSCs decreased with the increase in passage number. It was also revealed that VEGF increased surface expression and mRNA level of CXCR4 in USSCs, while IGF-1 decreased its expression. When VEGF and IGF-1 were administered simultaneously, CXCR4 expression was increased, but the expression level was less than VEGF alone. Finally, it was shown that over-expression of CXCR4 enhanced the migratory capacity of USSCs. The increase of CXCR4 expression, here caused by VEGF in USSCs, can improve the efficacy of stem cell therapy and transplantation after long-term culture of stem cells before clinical use.