Eukaryotic cells have evolved a number of survival tactics and quality control pathways that are able to counter intrinsic error-prone mechanisms and allow for maintenance of cellular homeostasis in the face of external stresses. This review will discuss the role of two cellular eukaryotic processes that are vital for maintenance of cellular homeostasis – 1) the nonsense-mediated mRNA decay (NMD) pathway and 2) the transient formation of stress granules (SG) – and explore the current literature on their roles in antiviral defence. Within the NCCR RNA & Disease, the laboratories of Proffs. O. Mühlemann and Volker Thiel teamed up to unravel the roles of NMD and SGs, and their interconnections in defending cells from alphavirus and coronavirus infections.