Host genetic variation in components of both specific and innate immune responses affects susceptibility to viral infections. Innate immunity provides the first line of defense, and the development of adaptive immunity is stimulated by innate responses. Pathogen recognition receptors (PRRs) initiate signaling pathways that result in the production of antiviral interferons and cytokines. Mutations or genetic variants (polymorphisms) have been recognized in several factors of innate immunity. Notably, human populations from distinct geographic areas have different frequencies of immune gene variants. The genetic susceptibility may vary from life-threatening manifestations of specific virus infections to a moderately increased frequency of nonsevere infections. Although the innate immunity is nonspecific by nature, the reactions are stereotypic for viral infections compared with bacterial infections. Even infections caused by specific viruses can be differentiated from each other based on the innate immune response. Host response pattern determination by expression analysis of a predefined set of genes is a novel strategy in the diagnosis of virus infections. Another strategy in differentiating viral and bacterial infections from each other could be the determination of a single marker, such as myxovirus resistance protein A (MxA), which is generally induced by viruses but not by bacteria. Host response analysis could also be used in monitoring infections and antiviral treatment, but applications for routine use are not yet available. Certain host gene variants correlate with the prognosis of infection. Currently, for instance, interleukin (IL) 28B genotyping is used to aid in hepatitis C treatment decisions.