To survive adverse and ever-changing environmental conditions, an organism must be able to adapt. It has long been established that the cellular reaction to stress includes the upregulation of genes coding for specific stress-responsive factors. In the present study, we demonstrate that during the early steps of the heat stress response, 25% of the Arabidopsis seedling transcriptome is targeted for rapid degradation. Our findings demonstrate that this process is catalyzed from 5' to 3' by the cytoplasmic exoribonuclease XRN4, whose function is seemingly reprogrammed by the heat-sensing pathway. The bulk of mRNAs subject to heat-dependent degradation are likely to include both the ribosome-released and polysome associated polyadenylated pools. The cotranslational decay process is facilitated at least in part by LARP1, a heat-specific cofactor of XRN4 required for its targeting to polysomes. Commensurate with their respective involvement at the molecular level, LARP1 and XRN4 are necessary for the thermotolerance of plants to long exposure to moderately high temperature, with xrn4 null mutants being almost unable to survive. These findings provide mechanistic insights regarding a massive stress-induced posttranscriptional downregulation and outline a potentially crucial pathway for plant survival and acclimation to heat stress.