The interferon (IFN) system is the first line of defense against viral infection in vertebrates. It is well known that IFN synthesis is induced by viral infection and secreted IFN act upon as yet uninfected neighboring cells to prepare them for combating oncoming virus infection. The products of IFN-stimulated genes (ISG), which number in hundreds, mediate this antiviral action of IFN. Recent evidence suggests that many of these genes are also induced directly by double-stranded RNA (dsRNA), a common byproduct of virus infection, or by other viral products. We refer to this family of genes, on which this article is focused, as viral stress-inducible genes (VSIG). First, we will discuss the different signaling pathways that lead to induce transcription of these genes in response to different agents. Second, we will review the available information about the inducibility of different VSIG by IFN, dsRNA, and viruses. In this article, we will review the functions of proteins encoded by selected members of the VSIG family. Because most of these proteins affect many aspects of cellular physiology, the information presented here is important for understanding not only the nature of host response to virus infection but also cellular responses to cytokines, such as IFN and exogenous dsRNA, which is known to signal through Toll-like receptor 3 (TLR3). Finally, we will present a future perspective and point out the main gaps of our knowledge in the field.