Cells respond to a variety of stressors by activating two major coordinated signaling networks to restore homeostasis: the unfolded protein response (UPR) and the integrated stress response (ISR). The UPR is activated when three ER sensors, ATF6, IRE1, and PERK, detect the accumulation of misfolded and unfolded proteins in the ER. Upon ER stress, ATF6 is transported to the Golgi apparatus, where it is cleaved. The released cytosolic fragment of ATF6 (ATF6f) then enters the nucleus and induces UPR gene expression. Upon activation, IRE1α dimerizes and autophosphorylates its kinase domain. The activated endoribonuclease domain excises a small intron from Xbp1 mRNA, producing XBP1s, a transcription factor that induces the UPR target genes. IRE1α also degrades select mRNAs (Regulated IRE1-dependent decay [RIDD]), ultimately reducing the protein-folding load. PERK activation leads to the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α), resulting in a global reduction in protein translation to prevent further ER burden, but paradoxically allowing selective translation of ATF4 that upregulates stress response genes. PERK is also a part of the ISR. The ISR integrates stress signals beyond the ER. In addition to PERK, three other kinases, PKR, HRI, and GCN2, can also phosphorylate eIF2α in response to viral infection, heme deficiency/mitochondrial dysfunction, and amino acid starvation, respectively. These inputs converge to modulate translation and reprogram gene expression, promoting cellular adaptation, or, if stress is severe, initiating programmed cell death. The study by Auyeung and colleagues (1) indicates that pathological cellular stress responses can impair alveolar epithelial differentiation.