This chapter discusses chemokines and their receptors in the evolution of viral infectious diseases of the central nervous system (CNS). Infection of the human CNS with many different viruses or infection of the rodent CNS induces vigorous host-inflammatory responses with recruitment of large numbers of leukocytes, particularly T lymphocytes and macrophages. Chemokines coordinate trafficking of peripheral blood leukocytes by stimulating their chemotaxis, adhesion, extravasation, and other effector functions. In view of these properties, research efforts have turned increasingly to the possible involvement of chemokines in regulating both peripheral tissue and CNS leukocyte migration during viral infection. The biological effects of chemokines are mediated via their interaction with receptors belonging to the family of seven transmembrane (7TM)-spanning, G-protein coupled receptors (GPCRs). In the normal mammalian CNS, the number of leukocytes present in the brain is scant. However, these cells are attracted to, and accumulate in, a variety of pathologic states, many involving viral infection. Although leukocyte migration into local tissue compartments, such as the CNS, is a multifactorial process, it has become clear that chemokines are pivotal components of this process, providing a necessary chemotactic signal for leukocyte recruitment.