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Chemokines (chemotactic cytokines) are a family of proteins that mediate recruitment and precise positioning of leukocytes in different anatomical locations, and as such are central to the immune response. Despite their importance, there are no Food and Drug Administration–approved therapies targeting chemokines or their receptors to treat inflammatory diseases.1,2 It has become clear that one of the primary reasons for this failure is the lack of a comprehensive understanding of basic chemokine biology.Chemokines function by binding to G protein–coupled chemokine receptors on the surface of leukocytes and activating the cell motility machinery that promotes cell movement. However, and of relevance to this perspective, chemokines, with few exceptions, bind to a second type of receptor—glycosaminoglycans (GAGs). A number of papers have demonstrated that this interaction is critical for the ability of chemokines to mediate leukocyte recruitment.3–7 In fact, it has been suggested that some chemokines, such as CCL18, do not function through chemokine receptors, but rather via GAG binding.8 The importance of this interaction to chemokine function is demonstrated by the evolution of proteins that inhibit chemokine:GAG interactions. These chemokine-binding proteins are produced by mammals, arachnids, and viruses to stop excessive inflammation and facilitate immune evasion.9–16 Despite this knowledge, the importance of chemokine:GAG interactions is not fully understood. In this perspective, we will outline a number of emerging concepts and unanswered questions that are being explored to further understand the role of chemokine:GAG interactions in regulating leukocyte recruitment.