The IFN system is a major mechanism by which many viruses evade the cellular antiviral response. DENV and ZIKV can suppress Type I IFN signaling, but the exact mechanisms remain to be fully understood. Moreover, emerging literature indicates that the type I IFN system mediates antiviral immunity in a highly context-specific manner depending on the virus, cell type, and host species. Therefore, we have been using our mouse models to understand the mechanisms by which type I IFN contributes to antiviral immunity during DENV and ZIKV infection. We have previously determined that type I IFN production is regulated by two signaling pathways: the STAT1-dependent and the STAT1-independent pathways. We have defined the latter mechanism of protection against DENV infection to be the type I IFN receptor-STAT2 pathway, and revealed that the type I IFN receptor-STAT2 pathway, in the absence of STAT1, modulates type I IFN production and interferon-stimulated gene (ISG) response in a delayed manner. Studies are underway to define the particular interferon regulatory factor and ISG mechanisms through which both the STAT1-dependent and STAT2-independent pathways contribute to protection vs. pathogenesis using both mouse models and human cell culture models.