Type I interferons (IFN-Is) are highly effective mediators of innate and adaptive immune responses against viruses. They mediate their wide range of effects predominantly through a canonical signalling complex, interferon-stimulated gene factor 3 (ISGF3). This complex consists of the signal transducer and activator of transcription 1 (STAT1), STAT2 and the interferon regulatory factor 9 (IRF9). In recent years it has become clear that non-canonical IFN-I signalling in the absence of individual components of the ISGF3 complex has divergent effects on the antiviral host response against viruses and the outcome of infection. We have recently shown that the three components of the ISGF3 complex play distinct roles in the antiviral immune response against lymphocytic choriomeningitis virus (LCMV). In contrast to wild type (WT) mice that clear LCMV, STAT1-deficient mice develop a lethal wasting disease following peripheral infection. The lethal disease requires STAT2- and IRF9-dependent IFN-I signalling and is mediated by CD4+ T cells. By contrast, mice deficient for either STAT2 or IRF9 survive infection but are unable to clear LCMV and instead develop a chronic infection. Both, the chronic infection and lethal wasting disease are driven by dysregulated ISGF3-independent IFN-I signalling. Understanding how IFN-Is mediate their diverse effects independently of ISGF3 is a critical step in optimizing their use as therapeutic agents.