Regulation of mRNA steady‐state levels is important in controlling gene expression particularly in response to environmental stimuli. This allows cells to rapidly respond to environment changes. The highly conserved nonsense‐mediated mRNA decay (NMD) pathway was initially identified as a pathway that degrades aberrant mRNAs. NMD is now recognized as a pathway with additional functions including precisely regulating the expression of select natural mRNAs. Majority of these natural mRNAs encode fully functional proteins. Regulation of natural mRNAs by NMD is activated by NMD targeting features and environmental cues. Here, we show that Saccharomyces cerevisiae strains from three genetic backgrounds respond differentially to NMD depending on the environmental stimuli. We found that wild type and NMD mutant W303a, BY4741, and RM11‐1a yeast strains respond similarly to copper in the environment but respond differentially to toxic cadmium. Furthermore, the PCA1 alleles encoding different mRNAs from W303a and RM11‐1a strains are regulated similarly by NMD in response to the bio‐metal copper but differentially in response to toxic cadmium.