The chemokines are a large family of small signaling proteins that bind to G-protein-coupled receptors (GPCRs) on target cells and mediate the directional migration of immune cells into sites of infection or inflammation. The large DNA viruses, particularly the poxviruses and herpesviruses, have evolved several mechanisms to corrupt the normal functioning of the chemokine network. Two strategies rely on mimicking chemokines or chemokine receptors. A third strategy involves the production of secreted chemokine-binding proteins (CKBPs) that exhibit no sequence similarity to any known host proteins, yet function to competitively bind and inhibit the interactions of chemokines with cognate receptors. Each strategy has provided unique insights into the elusively complex world of the chemokines. Here, we focus on recent advances made in the understanding of secreted CKBPs encoded by poxviruses and herpesviruses. A better understanding of how viral CKBPs function to manipulate the immune response may provide further clues as to how to develop specific therapeutic agents to abrogate chemokine-mediated disease conditions.