Mast cells are multifunctional, tissue-dwelling cells that have been traditionally associated with the allergic response. There is a growing interest in the role of chemokines and their receptors in mast cell tissue localization and function. The chemokines CXCL9, CXCL10, and CXCL11 interact with CXCR3 which is highly expressed on mast cells and monocytes. CXCR3 is a pertussis toxin sensitive, G protein-coupled receptor that is known to exist in at least 2 other isoforms, namely CXCR3-B and CXCR3-alt. CXCR3-B is thought to be pertussis toxin insensitive and also interacts with another chemokine, CXCL4. We have evidence derived from the monocytic cell line model, THP-1, that CXCL4 induces chemotaxis and activates actin polymerisation in a pertussis toxin sensitive manner, suggesting that CXCR3-B is actually pertussis toxin sensitive. Using cultured mast cells from CD133+ precursors derived from human cord blood we are investigating the expression of CXCR3 versus variant CXCR3 isoforms. To better understand how CXCR3 ligands can achieve selectivity, we are exploring differences in the phosphorylation profile of proteins mediated by the PI3K/PKB pathway and receptor tyrosine kinases using phosphoprotemic approaches as well as differences in Ca2+ influx/release. We are also exploring potential differences in functional responses such as degranulation and actin polymerisation. Recent evidence has discovered that in addition to CXCR3, CXCL11 also interacts with another chemokine receptor CXCR7. We have found that whilst CXCR7 is highly expressed on the mast cell line HMC-1, it is not detectable on the surface of human cord blood mast cells.