A general pathway of mRNA turnover has been described for yeast in which the 3' poly(A) tail is first deadenylated to an oligo(A) length, leading to decapping and subsequent 5'-3' exonucleolytic decay. The unstable MFA2 mRNA and the stable PGK1 mRNAs both decay through this pathway, albeit at different rates of deadenylation and decapping. To determine the regions of the mRNAs that are responsible for these differences, we examined the decay of chimeric mRNAs derived from the 5' untranslated, coding, and 3' untranslated regions of these two mRNAs. These experiments have led to the identification of the features of these mRNAs that lead to their different stabilities. The MFA2 mRNA is unstable solely because its 3' UTR promotes the rates of deadenylation and decapping; all other features of this mRNA are neutral with respect to mRNA decay rates. The PGK1 mRNA is stable because the sequence context of the PGK1 translation start codon and the coding region function together to stabilize the transcript, whereas the PGK13' UTR is neutral with respect to decay. Importantly, changes in the PGK1 start codon context that destabilized the transcript also reduced its translational efficiency. This observation suggests that the nature of the translation initiation complex modulates the rates of mRNA decapping and decay.