Pathogen-host interaction studies have demonstrated the importance of host factors in the pathogenesis of infectious disease. An emerging theme is that polymorphisms in the genes encoding these factors can influence the host response to infection and the course of disease. Genetic variation affecting interferon lambda (IFN-λ) expression is now known to influence the outcome of both hepatitis C virus and herpes simplex virus type 1 infection in humans. IFN-λ is expressed at higher levels in organs with high epithelial cell content such as the respiratory and gastrointestinal tracts. Interestingly, data from animal models show that IFN-λ contributes to host control of viruses infecting these sites, including influenza A virus, severe acute respiratory syndrome coronavirus, and rotavirus. Furthermore, defective IFN-λ production by humans with asthma impairs the control of rhinovirus infection. We hypothesize that genetic variation of IFN-λ could potentially influence the course of disease during infection with many viruses that infect epithelial cells.