Abstract: The degradation of mRNA in the yeast Saccharomyces cerevisiae takes place through several related pathways. In the most general mRNA-decay pathway, that of poly(A)-dependent decay, the normal shortening of the poly(A) tail on an mRNA molecule by deadenylation triggers mRNA decapping by the enzyme Dcp1p, followed by exonucleolytic digestion by Xrn1p. A specialized mRNA-decay pathway, termed nonsense-mediated decay, comes into play for mRNAs that contain an early nonsense codon. This pathway operates through the Upf proteins in addition to Dcp1p and Xrn1p. Previously, we identified a different specialized mRNA-decay pathway, the initiation-mediated decay pathway, and showed that it affects two Hsp70 heat-shock mRNAs under conditions of slowed translation initiation. Here we report that initiation-mediated mRNA decay also works through the Dcp1 and Xrn1 enzymes, and requires ongoing transcription by RNA polymerase II. We show that several other heat-shock mRNAs, including two from the Hsp90 gene family and three more from the Hsp70 gene family, are also subject to initiation-mediated decay, whereas a variety of non-heat-shock mRNAs are not affected.