Interferons are the antiviral early inflammatory proteins produced in the cells in response to the infectious agents. The characterization of the interferon genes, their expression, and their function was advanced with the development of novel techniques in molecular and cellular biology. Using genetically modified mice revealed the critical role of the interferons in innate and acquired immune response. The critical steps and discovery that lead to the understanding of the interferon system and its role in the antiviral immune response are summarized in this chapter.