Here we demonstrate that the ER stress response, in particular the ire-1 arm, is activated upon exposure of C. elegans and mammalian cells to PFTs. We demonstrate for the first time that the ire-1 -xbp-1 arm of the UPR (and to a lesser extent the atf-6 arm) is functionally important for defense against a pathogenic attack since loss of this pathway leads to animals hypersensitive to PFT, but not to other toxic insults. Furthermore, we demonstrate that activation of the ire-1-xbp-1 pathway by PFT requires p38 MAPK and its associated MAPK kinase and that the in vivo response of the UPR to a PFT can be separated from its response to unfolded proteins. These results indicate that activation of the UPR plays an important role in cellular defenses against pathogens.