The importance of chemokines and their receptors during infection, which initially had been inferred from their ability to induce leukocyte chemotaxis in vitro, has now been firmly established by direct genetic evidence in mice. However, recent evidence indicates that chemokines mediate not only specific leukocyte trafficking to sites of infection, as expected, but in addition, have surprising roles in regulating T helper cell polarization. Even more unexpectedly, HIV and Plasmodium vivax have been shown to use specific chemokine receptors as cell entry factors, facilitating rather than opposing transmission and progression of infectious disease. Further, most poxviruses and herpesviruses encode chemokine and/or chemokine receptor homologues which have been copied from the host and adapted for a variety of purposes, including evasion of the immune system, viral dissemination and possibly even tumorigenesis and angiogenesis. These types of viruses also encode three classes of secreted, structurally unique proteins that function as potent chemokine scavengers. The discovery of virus-encoded chemokines and chemokine receptors is significant with respect to both basic mechanisms of disease and clinical applications. Antichemokines (receptor antagonists and chemokine scavengers) provide powerful evidence that the chemokine system is important in anti-microbial host defense. Moreover, novel or unusual functions of viral chemokines and chemokine receptors may point to unrecognized functions for their host counterparts. Finally, viral anti-chemokines have the potential to be exploited therapeutically in diseases marked by chemokine expression and inappropriate inflammation. The aim of this article is to provide basic facts, current concepts and emerging unanswered questions for how host and microbial chemokine systems influence infection, focusing mainly on genetic evidence. Other biological processes regulated by the molecules discussed here are reviewed in separate articles in this volume. In addition, we will describe emerging technologies for blocking the chemokine system, which may be useful in HIV/AIDS and possibly other infectious diseases and inflammatory conditions.