Plants rely heavily on an adaptive RNA degradation system mediated by an RNA interference mechanism to combat viral infection, whereas mammals fight infection with specific antibodies and lymphocytes that are adapted to specific viral antigens, and also employ nonadaptive defenses, such as production of interferons (IFNs) that block viral replication and stimulate the host immune response. Therefore, the IFN system represents an integral part of the mammalian antiviral innate immunity, and it is not surprising to find that cellular, IFN-regulated microRNAs contribute to this antiviral defense. In contrast, virus-encoded microRNAs target host cell factors that are either required for the induction of IFNs after pathogen recognition, or are involved in the cellular responses to these pleiotropic cytokines.