Interferon (IFN) response is the first line of host defense against virus infection. The recent years have witnessed tremendous progress in understanding of fish IFN antiviral response. Varied number of IFN genes has been identified in different fish species but obviously, they do not show a one-to-one orthologous relationship with mammalian IFN homologs. These genes are divided into two groups with different abilities to induce downstream gene expression through binding to different receptor complexes. Consistently, some fish IFN-stimulated genes such as Mx and PKR have been confirmed for their antiviral effects. In this review, we focus on how fish cells respond to IFNs and how fish IFNs are triggered through TLR pathway and RLR pathway. We highlight the roles of IRF3 and IRF7 in activation of fish IFN response. In addition, the unique mechanisms underlying IRF3/7-dependent fish IFN response and auto-regulation of fish IFN gene expression are discussed. (C) 2012 Elsevier Ltd. All rights reserved.