The outcome after infection with the human immunodeficiency virus type 1 (HIV-1) is a complex phenotype determined by interactions among the pathogen, the human host and the surrounding environment. An impact of host genetic variation on HIV-1 susceptibility was identified early in the pandemic, with a major role attributed to the genes encoding class I human leukocyte antigens (HLA) and the chemokine receptor CCR5. Studies using genome-wide data sets have underscored the strength of these associations relative to variants located throughout the rest of the genome. However, the extent to which additional polymorphisms influence HIV-1 disease progression, and how much of the variability in outcome can be attributed to host genetics, remain largely unclear. Here we discuss findings concerning the functional impact of associated variants, outline methods for quantifying the host genetic component and examine how available genome-wide data sets may be leveraged to discover gene variants that affect the outcome of HIV-1 infection.