Chemokines are small cytokines that are part of a large family of molecules that bind to G-protein coupled receptors, which, as a family, are the most widely targeted group of molecules in the treatment of disease. Chemokines are critical for recruiting and activating the cells of the immune system during inflammation especially during viral infections. However, a number of viruses including the large herpes virus human cytomegalovirus (HCMV) encode mechanisms to impede the effects of chemokines or has gained the ability to use these molecules to its own advantage. The Human Cytomegalovirus (HCMV)-encoded chemokine receptor US28 is the best characterized of the four unique chemokine receptor-like molecules found in the HCMV genome. US28 has been studied as an important virulence factor for HCMVmediated vascular disease and, more recently, in models of HCMV-associated malignancy. US28 is a rare multichemokine family binding receptor with the ability to bind ligands from two distinct chemokine classes. Ligand binding to US28 activates cell-type and ligand-specific signaling pathways leading to cellular migration, which is an important example of receptor functional selectivity. Additionally, US28 has been demonstrated to constitutively activate phospholipase C (PLC) and NF-κB signaling pathways. Understanding the structure/function relationships between US28, its ligands and intracellular signaling molecules will provide essential clues for effective pharmacological targeting of this multifunctional chemokine receptor.