Correctly folding proteins is a severely complicated process that fails at times, despite the controlled environment of the ER and numerous molecular helpers. Under normal conditions, these misfolded proteins are degraded through the ER-associated degradation (ERAD) mechanism. However, various physiological or environmental stressors can inhibit or overwhelm these normal mechanisms resulting in an increase in the amount of misfolded proteins, which trigger the Unfolded Protein Response (UPR). Organisms have evolved the UPR to handle this ER stress and suppress the toxicity of accumulated misfolded proteins (proteotoxicity). In mammals the UPR attenuates protein synthesis through PERK/PEK1 and increases transcription of folding and ERAD components through activation of potent transcription factors through IRE1 splicing of XBP1 mRNA and ER-stress cleavage of ATF-6. These events ultimately augment folding and enhance degradation capacity of the organelle. In C. elegans, the UPR also activates transcriptional regulators that reduce protein synthesis and increase the number of components necessary to deal with misfolded proteins.