Foxc1 and Foxc2 transcription factors are required for vascular development. However, the molecular mechanisms by which Foxcl and Foxc2 control angiogenesis, the growth of new blood vessels from pre-existing vessels and capillaries, remain unknown. CXC chemokine ligand 12 (CXCL12) and its receptor, CXCR4, are critical for the process of angiogenesis, including the migration and tube formation of endothelial cells. Here we show that Foxcl and Foxc2 directly induce CXCR4 expression by activating its promoter in endothelial cells. Furthermore, Foxc1-deficient endothelial cells show a significant reduction in CXCR4 expression as well as CXCL12-stimulated migration. Taken together, these results provide novel evidence that Foxc transcription factors are important regulators of the chemotactic motility of endothelial cells through the induction of CXCR4 expression. (C) 2008 Elsevier Inc. All rights reserved.