Much progress has been made on how nonsense‐mediated mRNA decay (NMD), which we first described for humans in 1981, controls the quality of gene expression by detecting and rapidly degrading aberrant mRNAs that contain a premature termination codon1. Our studies of NMD have led to the discovery of the pioneer round of translation, the post‐splicing “mark” on newly synthesized mRNAs – later named the exon‐junction complex (EJC) with Melissa Moore – the mechanistically related and competing Staufen‐mediated mRNA decay pathway2,3, including new roles for SINEs4, and most recently a microRNA decay pathway5,6. We tracked individual cellular transcripts in collaboration with Rob Singer to confirm our results from the mid‐1990's indicating that NMD for a number of mRNAs occurs on the cytoplasmic side of the nuclear envelop7. Our data provide explicit evidence that proteins acquired by newly synthesized mRNAs in the nucleus, including the cap‐binding protein CBP80 and constituents of the EJC, are critical for mRNA quality control via translation in the cytoplasm. We have also described the molecular mechanism for how NMD targets are discriminated from other transcripts: the central NMD factor – the ATP‐dependent RNA helicase UPF1 – preferentially associates with mRNA 3′‐untranslated regions (3′ UTRs) in a way that correlates with 3′ UTR length and the presence of a 3′ UTR EJC8,9. Importantly, NMD also targets ~10% physiologic mRNAs that are key to maintaining cellular homeostasis in a changing environmental milieu. For example, we reported that a sufficient level of DNA damage induced by commonly used frontline chemotherapeutics inhibits NMD by triggering the caspase‐mediated cleavage of sub‐stochiometric amounts of UPF1, thereby upregulating the half‐lives of mRNAs that include those encoding proteins promoting apoptosis10. Notably, the modest inhibition of NMD promotes but is not sufficient for programmed cell death. These and other results will be discussed.Support or Funding InformationWork on nonsense‐mediated mRNA decay in the Maquat lab is supported by NIH R01 GM 059614 to L.E.M.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.