Viruses are prototypic obligate intracellular pathogens, and are therefore, by necessity, highly pre-adapted to surviving the host immune response. Nevertheless, host genetic factors remain an important determinant of disease outcome, particularly in the case of viruses that have encountered humans in the more recent past (e.g. human immunodeficiency virus). Recent studies have identified an increasingly rich network of functionally relevant polymorphic immune factors, including major MHC alleles, killer immunoglobulin-like receptors and functional chemokine receptor polymorphisms. Moreover, genetic variation is increasingly appreciated beyond the single genotype level, incorporating extended haplotypes as well as regions of segmental genetic duplication. These issues can be considered within an evolutionary perspective that acknowledges the crucial role of adaptive host-viral relationships in shaping both host and pathogen genetic diversity.