Chemokine receptors are found on cell surfaces and promote cellular migration by chemotaxis. The CC chemokine receptor 5 (CCR5) is used by the human immunodeficiency virus (HIV) to infect cells. Strategies that target human CCR5 are therefore being developed to prevent and treat HIV infection. Antiviral strategies that target a host element necessary for viral replication may be predicted to interfere with the function of that element and may therefore adversely affect the host. We conducted a review of the literature between November 2005 and April 2006 with a focus on articles addressing the genetics and function of CCR5, the effects of CCR5 deletion in human and murine systems, and treatment strategies for HIV infection that target this coreceptor. English-language articles in the human and murine literature published between March 1996 and April 2006 were identified through a search of MEDLINE using CCR5 as the search term. Relevant articles as judged by their titles and abstracts were reviewed in detail. In addition, based on our knowledge of the field and with permission, unpublished work was also reviewed. In this article, we explore the effects that targeting CCR5 may have on host defenses in individuals with immunity already compromised by HIV infection.