Updated project metadata. The heat shock response is an ancient and ubiquitous program allowing organisms to survive adverse environmental conditions. In S. cerevisiae, three transcription factors, Hsf1, Msn2 and Msn4, are thought to regulate the stress response. While Msn2/4 can be deleted, Hsf1 is essential. By combining the depletion of Hsf1 with the deletion of Msn2 and Msn4, we were able to switch off the central stress response. We show that the transcription factors Hsf1 and Msn2/4 follow different strategies and regimes: Whereas Msn2/4 are responsible for a broad metabolic response, Hsf1 triggers a direct chaperone response to stabilize and repair unfolded proteins. Exposure of cells lacking Msn2/4 and Hsf1 to thermal stress resulted in massive protein aggregation. Comparison with wildtype yeast revealed that among the proteins rescued by the stress response are many essential proteins.