Host genetic variation is presently estimated to account for about one-fourth of the observed differences in control of HIV across infected individuals. Genome-wide association studies have confirmed that polymorphism within the HLA class I locus is the primary host genetic contributor to determining outcome after infection. Here we progress beyond the genetic associations alone to consider the functional explanations for these correlations. In this process, the complex and multidimensional effects of HLA molecules in viral disease become apparent.