RNA silencing is a novel RNA-guided gene regulatory mechanism operational in a wide range of eukaryotic organisms from fission yeast, plants, to mammals. This article reviews the recent progress on aspects of RNA silencing that are related to its biological function as a conserved antiviral immunity of plants and animals, and highlights features of this novel antiviral response in invertebrate animals as compared to the known innate and adaptive immunities. Finally, we discuss evidence that suggests a natural antiviral role for RNA silencing in vertebrates as well as experimental approaches that may facilitate the identification of first mammalian viral suppressors of RNA silencing.