Chemokine biology has seen a renaissance in the almost two decades since the first discovery and characterization of a chemokine molecule, known as monocyte derived neutrophil chemotactic factor (Yoshimura et al., 1987) or neutrophil activating factor (Walz et al., 1987) and later renamed IL-8 and then CXCL-8. It is doubtful that those who originally described this novel factor had any idea of the explosion in immunology they had ignited. In short order, the two receptors for this factor were identified and cloned (Holmes et al., 1991; Murphy and Tiffany, 1991), and then similar molecules were discovered and characterized until, by 1997, an extensive constellation of ligands and receptors (key signaling molecules in the immune system) had been recognized (Baggiolini et al., 1997). Generally speaking, chemokines are released by cells to induce the migration of other cells that possess appropriate G-protein-coupled receptors towards higher chemokine concentrations (a process called chemotaxis). Chemokine activity is now understood to be the immune system's predominant type of internal signal for specific recruitment of particular cell types to important sites. This cell recruitment is essential for the innate immune system's inflammatory responses, for proper tissue development in organs of the cardiovascular, nervous, and immune systems, and for the activation as well as the specialized regional development of memory and effector lymphocytes in the adaptive immune system of the adult animal (Rot and von Andrian, 2004). Consequently, for some disorders of immunity the activities of various chemokines have become recognized as major potential therapeutic targets for diseases of many organ and tissue systems (Wang et al., 1998; Howard et al., 1999; Nickel et al., 1999), because their targeted disruption of leukocyte trafficking and intercellular communication would allow, by today's standards, specific and elegant modulation of the immune response. We will explore the biology of the CXC family of chemokines and receptors in three sections. The first section will discuss the structure, function, and history of the CXC chemokine ligands and receptors. In the second section we will discuss the biochemistry and cell biology underlying the signaling of these molecules. We will finish with a discussion of cellular trafficking and the roles these chemokines play in normal and pathological states, addressing potential therapeutic targets of this system. By the end of the article, the reader should have gained a solid understanding of the basic mechanisms of the CXC chemokine system, as well as some insight into the contributions of this signalling activity at the level of whole animal physiology. © 2005 Elsevier Inc. All rights reserved.