Chemokines were detected by virtue of chemotactic effects toward neutrophils in the late 1970s. During subsequent decades, it has become clear that their primordial role in vertebrate biology was to facilitate organogenesis, with particularly important functions in the central nervous system (CNS). In common with other developmentally relevant factors, chemokines and their G-protein-coupled receptors continue to be expressed in the adult CNS as neuromodulators. In our progress toward chemokine receptor blockade for treatment of inflammatory and infectious diseases, the CNS physiology of the chemokine system will need to be a material consideration. In some cases, the dual functions of the chemokine system in the periphery and in the CNS offer unique possibilities for disease treatment.