Recent studies have demonstrated that cells have evolved elaborate mechanisms to rid themselves of aberrant proteins and transcripts. The nonsense-mediated mRNA decay pathway (NMD) is an example of a pathway that eliminates aberrant mRNAs. In yeast, a transcript is recognized as aberrant and is rapidly degraded if a specific sequence, called the DSE, is present 3′ of a premature termination codon. Results presented here show that strains harboring the mof2-1, mof4-1, mof5-1, and mof8-1 alleles, previously demonstrated to increase the efficiency of programmed −1 ribosomal frameshifting, decrease the activity of the NMD pathway. The effect of the mof2-1 allele on NMD was characterized in more detail. Previous results demonstrated that the wild-type MOF2 gene is identical to the SUI1 gene. Studies on the mof2-1 allele of the SUI1 gene indicate that in addition to its role in recognition of the AUG codon during translation initiation and maintenance of the appropriate reading frame during translation elongation, the Mof2 protein plays a role in the NMD pathway. The Mof2p/Sui1p is conserved throughout nature and the human homolog of the Mof2p/Sui1p functions in yeast cells to activate NMD. These results suggest that factors involved in NMD are general modulators that act in several aspects of translation and mRNA turnover.