Nonsense-mediated RNA decay (NMD) is an evolutionarily conserved RNA quality control process that serves both as a mechanism to eliminate aberrant transcripts carrying premature stop codons, and to regulate expression of some normal transcripts. For a quality control process, NMD exhibits surprising variability in its efficiency across transcripts, cells, tissues, and individuals in both physiological and pathological contexts. Whether an aberrant RNA is spared or degraded, and by what mechanism, could determine the phenotypic outcome of a disease-causing mutation. Hence, understanding the variability in NMD is not only important for clinical interpretation of genetic variants but also may provide clues to identify novel therapeutic approaches to counter genetic disorders caused by nonsense mutations. Here, we discuss the current knowledge of NMD variability and the mechanisms that allow certain transcripts to escape NMD despite the presence of NMD-inducing features. This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA in Disease and Development > RNA in Disease RNA Turnover and Surveillance > Regulation of RNA Stability.