The extended family of chemokines regulates the activation of leukocytes and coordinates their trafficking to sites of inflammation and during immune surveillance. The heptahelical-receptor-binding and function of chemokines is thought to be governed by their interaction with cell surface proteoglycans, oligomer formation, naturally occurring antagonists and proteolytic processing. Recent studies reveal that heterophilic interactions between chemokines can significantly modify their biological activities and through these we can gain initial insights into the structural basis underlying this novel regulatory mechanism. Here, we propose the concept of a functional ‘interactome', constituted by a variety of heterophilic chemokine–chemokine interactions in particular microenvironments. This model could establish how signals conferred by various chemokines are integrated for the combinatorial control of leukocyte responses.