The discovery that chemokine receptors act as cofactors indispensable for HIV entry into target cells identified new targets for anti-retroviral therapy. However, much remains to be learned about the nature of their physiological role in the organism, as well as the molecular details of viral entry. The multitude of different receptors permitting HIV entry in vitro and their respective roles in vivo for entry, as well as their implication in distinct pathogenic events have added further complexity to this field of research. This review summarizes knowledge on HIV-coreceptors, their role under normal physiological conditions as well as in HIV pathogenesis and its implications on the development of concepts for the use of coreceptor targeting therapeutic approaches. An overview over antiviral ligands of chemokine receptors reported so far, as well as alternative strategies of antiviral interventions involving chemokine receptors is given.