The chemokine receptor gene, CCR5, has become a central theme in studies of host genetic effects on HIV-1 pathogenesis ever since the discovery that the CCR5 molecule serves as a major cell surface co-receptor for the virus. A growing number of genetic variants within the coding and 5' regulatory region of CCR5 have been identified, several of which have functional consequences for HIV-1 pathogenesis. Here we review the CCR5 literature describing CCR5 polymorphism and the functional ramifications that several of these variants have on HIV-1 infection and progression to AIDS. The multiplicity of CCR5 genetic effects on HIV-1 disease underscores the critical importance of this gene in controlling AIDS pathogenesis and provides the logic for develop-ment of therapeutic strategies that target the interaction of HIV-1 envelope and CCR5 in HIV-1 associated disease.