IBDs are characterized by increased influx of immune cells to the mucosa of genetically susceptible persons. Cellular migration to injury sites is mediated by chemokines. CXCL12 is a ubiquitous, constitutive chemokine that participates in stem cell proliferation and migration and mediates T lymphocyte migration to inflamed tissues. We have recently reported that CXCL12 and its receptor, CXCR4, are expressed in normal and more prominently, inflamed human intestinal mucosa. However, the interactions and roles of CXCL12 and its receptors, CXCR4 and the recently discovered CXCR7, in intestinal inflammation have not been defined. In the present study, we further dissected the effects of CXCL12 on lymphocytes in intestinal homeostasis and inflammation and delineated the interplay between CXCL12 and its receptors CXCR4 and CXCR7. To that end, fresh mononuclear cells were isolated from mucosa and PB of healthy or IBD patients. Phenotypical and functional assays were conducted using flow cytometry, Transwell migration chambers, and ELISA. The data show that CXCL12-mediated migration of T cells is CXCR4- but not CXCR7-dependent. T cell activation reciprocally regulates CXCR7 and CXCR4 expression and migratory capacity. IBD PBTs expressed more CXCR7 than normal PBTs. Finally, T cells attracted by CXCL12 are mostly of a memory phenotype. In conclusion, the present study suggests that the interplay between CXCL12 and its receptors affects homeostasis and inflammation in the intestinal mucosa.