Flaviviruses and coronaviruses have repeatedly emerged as major human pathogens, causing outbreaks with significant public health, economic, and societal impacts. Their continued emergence and re-emergence underscore the urgent need to better understand the host-specific determinants that shape susceptibility to infection and disease severity. Our research focuses on dissecting virus–host interactions that govern viral replication and immune control, with particular emphasis on interferon-mediated innate immune responses. We investigate how differences in interferon signaling pathways influence cellular permissiveness to infection and determine the efficiency of viral replication and spread. In parallel, we study host dependency factors that are exploited by flaviviruses and coronaviruses throughout their replication cycles, from viral entry and genome replication to assembly and egress. Identifying these essential host factors provides critical insight into conserved mechanisms of viral replication and reveals potential targets for host-directed antiviral strategies. Together, these interdisciplinary efforts aim to define key determinants of viral emergence and pathogenesis, improve our ability to predict infection outcomes, and inform the development of effective antiviral interventions that are robust to viral evolution.