Host genetic factors play a central role in determining the clinical phenotype of human diseases. Association between two polymorphic loci in human genome, human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptors (KIRs), and genetically complex infectious disease, particularly those of viral etiology, have been historically elusive. Hence, defining the influence of genetic diversity in HLA and KIRs on the outcome of viral infections has been extensively started in clinically well-defined cohort studies. HLA genes encode molecules which present antigenic peptide fragments to T lymphocytes as central players in adaptive immunity against infectious diseases. KIRs are expressed on natural killer cells which perform a crucial role in innate immunity to pathogen infection. The effector functions of NK cells such as direct killing of infected cells, cytokine production, and cross-talk with adaptive immune system depend on activation of NK cells, which is determined by their surface receptors. Among these receptors, KIRs, which interact with HLA class I, are mainly inhibitory and exhibit substantial genetic diversity. An extensive body of association studies indicates a role for HLA–KIRs interactions in infectious diseases, autoimmune disorders, cancer, transplantation, and reproduction. Various compound HLA-KIR genotypes appear to affect outcome of viral infections that suggests a role for HLA class I diversity in innate immunity as well as adaptive immune responses. The aim of this review is focusing on the impact of HLA and KIR alleles and different combinations of these alleles on clinical outcome of viral diseases to validate this proof-of-concept with respect to the therapeutic interventions.