Aberrant expression of chemokines and their receptors play causative roles in the pathophysiology of numerous autoimmune and inflammatory disease processes. Moreover, an integral step in HIV infection involves binding to chemokine receptors, and hence chemokines are intimately linked to HIV-related diseases. Therefore, chemokines and their receptors are excellent targets for developing drugs that are more specific and may be of benefit in the management of disease. Knowledge of the chemokine and chemokine receptor structures, and an understanding of the structural basis of their function are essential for structure-aided design of receptor decoys. Chemokine ligands bind their receptors with nanomolar (nM) affinity, and successful design of a small molecule antagonist should bind the receptor with similar high affinity and specificity. Chemokines bind receptors that belong to the 7-transmembrane class on leukocytes, and highly negatively charged proteoglycans that are present on the cell surface. Stru cture-function studies have identified regions in both the ligand and the receptor that mediate binding and activation. Structures of numerous chemokines have been solved though very little is known regarding receptor structures. This review will summarize the current knowledge on the structures, structure-function, and the efficacy of chemokine derivatives and functional domain peptides as antagonists, and discuss strategies for exploiting this information for designing decoys for inflammatory, autoimmune, and HIV-related diseases.