Both the beneficial and harmful roles of neutrophils are critically dependent on the capacity of the cell to undergo directed migration from the blood to local tissue sites. Because the CXC chemokine interleukin-8 (IL-8) is a powerful mediator of this process, its receptor is a reasonable target for development of treatments for neutrophil-mediated inflammation. However, this strategy has been complicated by the discovery of two distinct IL-8 receptors, CXCR1 and CXCR2, that are coexpressed on human neutrophils. Both are 7-transmembrane domain-type proteins functionally coupled to G proteins. Although both receptors bind IL-8 with high affinity, they differ in selectivity for other CXC chemokines, as well as in their regulation and signal transduction, but whether they also differ biologically is not yet clear.