CXCR4, CD133, CD44 and ABCG2 are representative transmembrane proteins expressed on the surfaces of normal and/or cancer stem cells. CXCR4 is co-expressed with POU5F1 in endodermal precursors and adult-tissue stem cells. CXCR4 is expressed in a variety of human tumors, such as breast cancer, prostate cancer, pancreatic cancer, and gastric cancer. CXCR4 is a G protein-coupled receptor (GPCR) for CXCL12 (SDF1) chemokine, and the CXCL12-CXCR4 signaling axis is involved in proliferation, survival, migration, and homing of cancer cells. Integrative genomic analyses of CXCR4 gene were carried out to elucidate the mechanisms of CXCR4 expression in stem cells, because CXCR4 is a key molecule occupying the crossroads of oncology, immunology, gerontology and regenerative medicine. Human CXCR4 promoter region with binding sites for HIF1alpha, ETS1, NF-kappaB and GLI was not conserved in mouse and rat Cxcr4 orthologs. Proximal enhancer region with palindromic Smad-binding sites, FOX-binding site, POU-binding site, triple SOX17-binding sites, bHLH-binding site, TCF/LEF-binding site, and double GFI1-binding sites was almost completely conserved among human, chimpanzee, mouse, and rat CXCR4 orthologs. TGFbeta, Nodal, and Activin signals induce CXCR4 upregulation based on Smad2/3 and FOX family members, such as FOXA2, FOXC2, and FOXH1. CXCR4 is expressed in endodermal precursors due to the existence of triple SOX17-binding sites around the POU-binding site instead of the POU5F1-SOX2 joint motif. Because CXCR4 is downregulated by p53-GFI1 signaling axis, p53 mutation in cancer stem cells leads to CXCR4 upregulation. CXCR4 is also upregulated by TGFbeta and Hedgehog signals in tumor cells at the invasion front. Small molecule compound or human antibody targeted to CXCR4 will be applied for cancer therapeutics focusing on cancer stem cells at the primary lesion as well as metastasis or recurrence niches, such as bone marrow and peritoneal cavity.