Viral infection of the central nervous system (CNS) poses unique challenges to the immune system with regards to controlling and eliminating the invading pathogen. These obstacles include the presence of a blood–brain barrier (BBB) that provides a physical and physiological barrier that is difficult for cells and molecules to cross, the absence of classic lymphatic drainage that may impair the generation of an adaptive immune response, and limited MHC class I or II expression on resident cells of the CNS, even during periods of neuroinflammation. In addition, the CNS is composed of a variety of highly specialized cells, many of which have limited renewal capacity, that represent potential targets of infection by numerous different viruses. Nonetheless, antigen-specific lymphocytes are ultimately able to accumulate within the CNS and contribute to defense by reducing or eliminating the invading viral pathogen. Alternatively, infiltration of activated cells of the immune system may be detrimental, as these cells can contribute to neuropathology that may result in long-term cellular damage or death. Understanding the mechanisms that govern leukocyte trafficking from the microvasculature into the CNS parenchyma is therefore critical for comprehending the molecular and cellular events that control neuroinflammation following infection by neurotropic viruses. Chemokines, small (8–10kDa) proteins expressed by almost all nucleated cell types, are divided into four subfamilies based upon the number and spacing of conserved cysteine residues present within the amino terminus of the protein. Chemokine function is controlled through often promiscuous signaling via seven transmembrane G-protein-coupled receptors. While initially characterized as important in inflammation by targeting distinct leukocyte populations, chemokines are now considered critical mediators of a variety of biological processes, including development, tissue homeostasis, and coordinated immune responses during viral infection.