Both HCMV and MCMV target PERK-ATF4 and IRE1-XBP-1 pathways to selectively activate a subset of UPR genes. Interestingly, although XBP-1 mRNA was spliced upon infection with HCMV, its target genes involved in protein degradation were not expressed. Moreover, ATF6 cleavage was inhibited in infected cells, but chaperone genes were expressed in an ATF6 independent manner. HCMV also harnesses the PERK Cinoxacin pathway of the UPR to manipulate cellular metabolism for its benefit. Recently we identified the late proteins M50 and UL50 encoded by MCMV and HCMV, respectively, to interact with IRE1. This interaction leads to IRE1 degradation. Owing to the multifaceted roles played by IRE1 following activation, which include the splicing of XBP-1 mRNA, RIDD, JNK activation and triggering innate immunity sensors, it is not clear which of all of these have the potential to affect viral propagation in infected cells. This can be address by investigating the specific roles of the elements downstream to IRE1. Here we rigorously explored the role of XBP-1 in MCMV infection in vitro and in vivo. The UPR in the context of viral infection can serve the pathogen by improving the survival of host cells under enhanced protein load in the ER and by ensuring the fidelity of viral glycoprotein synthesis and folding. On the other hand, the UPR may serve to the IOX2 advantage of the host by promoting the production of antiviral cytokines such as interferons and proinflammatory responses, such as the NF-kb pathway, and directing the infected cells to apoptosis through the ER stress pathway. The discovery that MCMV targets IRE1, the most conserved and central element of the UPR, strongly implies that the UPR serves better the host and thus MCMV may tolerate the compromise in ER functions for the sake of other activities governed by IRE1. The nuclease activity of IRE1 is not restricted to the mRNA of XBP-1. While XBP-1 mRNA undergoes splicing by IRE1, other RNA molecules are subjected to degradation through RIDD. This degradation can generate small RNA molecules that activate the RIG-I sensor and downstream proinflammatory signaling cascades. RIDD also has controversial roles in promoting ER stress mediated apoptosis, probably depending on the cell type and the exact experimental conditions. Inhibitors of IRE1 were demonstrated to promote cell death in B cell malignancies, while preserving viability of b islet cells.