The integrated stress response (ISR) is a signaling pathway initiated by stress-activated eIF2α kinases, which respond to various stress signals such as amino acid deprivation and mitochondrial stress. This response attenuates general mRNA translation and stimulates the preferential translation of specific factors to orchestrate an adaptive gene expression program. Recent advances in understanding the ISR during metabolic stress adaptation include its activation mechanisms in response to amino acid deprivation and mitochondrial stress, and its impact on amino acid metabolic pathways and disease models. The ISR has been linked to various diseases, including metabolic, pulmonary, and neurological disorders, and its loss or excessive activation can contribute to disease phenotypes. Recent studies have also highlighted the role of the ISR in amino acid biosynthesis and the maintenance of cellular redox potential, particularly through the induction of enzymes involved in serine and cysteine biosynthesis. Additionally, the mechanisms of GCN2 activation during amino acid deprivation have been explored, revealing multiple activation models involving uncharged tRNAs and ribosome stalling. The relationship between GCN2 and amino acid deprivation response is complex, with some conditions of amino acid deprivation not activating GCN2. Furthermore, the ISR can be regulated independently of eIF2α kinase activity, as seen in mutations in the eIF2B complex and X-linked intellectual disability syndromes. The ISR also plays a role in the mitochondrial stress response, with different eIF2α kinases mediating the response depending on cell type and the nature of mitochondrial dysfunction. Overall, the ISR integrates a broad set of stress conditions and impacts cellular adaptation to both amino acid deprivation and mitochondrial stress.The integrated stress response (ISR) is a signaling pathway initiated by stress-activated eIF2α kinases, which respond to various stress signals such as amino acid deprivation and mitochondrial stress. This response attenuates general mRNA translation and stimulates the preferential translation of specific factors to orchestrate an adaptive gene expression program. Recent advances in understanding the ISR during metabolic stress adaptation include its activation mechanisms in response to amino acid deprivation and mitochondrial stress, and its impact on amino acid metabolic pathways and disease models. The ISR has been linked to various diseases, including metabolic, pulmonary, and neurological disorders, and its loss or excessive activation can contribute to disease phenotypes. Recent studies have also highlighted the role of the ISR in amino acid biosynthesis and the maintenance of cellular redox potential, particularly through the induction of enzymes involved in serine and cysteine biosynthesis. Additionally, the mechanisms of GCN2 activation during amino acid deprivation have been explored, revealing multiple activation models involving uncharged tRNAs and ribosome stalling. The relationship between GCN2 and amino acid deprivation response is complex, with some conditions of amino acid deprivation not activating GCN2. Furthermore, the ISR can be regulated independently of eIF2α kinase activity, as seen in mutations in the eIF2B complex and X-linked intellectual disability syndromes. The ISR also plays a role in the mitochondrial stress response, with different eIF2α kinases mediating the response depending on cell type and the nature of mitochondrial dysfunction. Overall, the ISR integrates a broad set of stress conditions and impacts cellular adaptation to both amino acid deprivation and mitochondrial stress.