Interferon was described by Isaacs and Lindenmann in 1957 [1, 2], and its importance in antiviral host defense was first demonstrated in 1960 [3]. Virelizier and Gresser were the first to show that endogenous interferon type I mediated one example of genetically determined resistance to a viral infection, when they found that injection of an anti-type I interferon IgG overcame the innate resistance of C3H and A/J mice to mouse hepatitis virus [4]. These results were then extended by Haller and colleagues, using the same anti-IFN IgG to render a Mendelian-determined resistant strain of mice fully susceptible to the lethal effects of influenza A virus [5, 6]. Molecular confirmation of these data came through the definition of murine models lacking the type I interferon receptor and relevant downstream signaling molecules [7–9] and the study of human inborn errors of immunity, beginning with the identification of inherited complete STAT1 deficiency in 2003 [10, 11].