The chemokine receptor CCR5 was identified in 1996 as a crucial host factor exploited by HIV for cell entry. CCR5 presumably functions normally in antimicrobial host defense because it generally mediates leukocyte chemotactic responses; however, evidence of antimicrobial functions for CCR5 in humans has been elusive. Recently, genetic analyses in mice and humans have provided strong evidence for the CCR5 control of infection by West Nile virus (WNV), a re-emerging pathogen capable of causing fatal encephalitis. Thus, the same receptor can benefit or harm the host, depending on the virus. Although CCR5 might be a logical target for new drug development in HIV/AIDS, the benefits of blocking CCR5 could carry the cost of an increased risk of WNV disease in co-infected patients.