Human immunogenetic studies beginning in 1996 have produced clear evidence that initial acquisition of HIV-1 infection can be effectively blocked by homozygosity for a 32-bp deletion (Δ32) in the open reading frame of the beta (C-C motif) chemokine receptor 5 (CCR5) and further inhibited by the Δ32 heterozygous genotype or by Δ32 in combination with another mutation that also introduces a premature stop codon in CCR5. Conversely, homozygosity for the CCR2-CCR5 HHE haplotype defined by several single-nucleotide polymorphisms (SNPs) appears to enhance HIV-1 acquisition. The two closely related CCR2-CCR5 haplotypes HHE and HHG*2 (=CCR5-Δ32) and probably others [e.g., HHF*2 (=CCR2-64I)] are also associated with varying rates of HIV-1 disease progression against certain ethnic backgrounds. Additional but less consistent associations with both HIV-1 infection and disease progression have been documented for SDF-1, RANTES (SCYA5), CX3CR1, and MIP-1α polymorphisms within the chemokine receptor and ligand system. Both chance association and population heterogeneity probably account for some of the inconsistencies. More recent recognition of CCR2-CCR5 haplotype-mediated effects on HIV-1 RNA concentration implies that CCR polymorphisms are important early determinants of the virus–host equilibrium. Evolving usage of chemokine receptors by HIV-1 may cloud the interpretation of newly acquired data and impede translation of this research into improvements in clinical care. The functional complexity of the chemokine system and its interactions with other host and viral factors calls for a comprehensive analytic approach to the elucidation of immunogenetic influences on HIV/AIDS and vigilance for effects of viral adaptation.