One major pathway of mRNA decay in yeast occurs by deadenylation-dependent decapping, which exposes the transcript to 5' to 3' exonucleolytic degradation. We show that a second general pathway of mRNA decay in yeast occurs by 3' to 5' degradation of the transcript. We also show that the SKI2, SKI3, SKI6/RRP41, SKI8 and RRP4 gene products are required for 3' to 5' decay of mRNA. The Ski6p/Rrp41p protein has homology to the Escherichia coli 3' to 5' exoribonuclease RNase PH, and both the Ski6p/Rrp41p and Rrp4p proteins are components of a multiprotein complex, termed the exosome, that contains at least three polypeptides with 3' to 5' exoribonuclease activities. These observations suggest that the exosome may be the nucleolytic activity that degrades the body of the mRNA in a 3' to 5' direction, and the exosome's activity on mRNAs may be modulated by Ski2p, Ski3p and Ski8p. Blocking both 3' to 5' and 5' to 3' decay leads to inviability, and conditional double mutants show extremely long mRNA half-lives. These observations argue that efficient mRNA turnover is required for viability and that we have identified the two major pathways of mRNA decay in yeast.