The study investigates the mechanism by which ATF4 mRNA translation is regulated in response to eIF2 phosphorylation in mammalian cells. ATF4, a transcriptional regulator, is upregulated during cellular stress to activate genes involved in stress response. The 5' leader region of the *ATF4* mRNA contains two upstream ORFs (uORFs) that contribute differentially to ATF4 translation. UORF1 is a positive-acting element that facilitates ribosome scanning and reinitiation at downstream coding regions, while UORF2 is an inhibitory element that blocks ATF4 expression in non-stressed conditions. During stress, phosphorylation of eIF2 reduces eIF2-GTP levels, delaying reinitiation and allowing ribosomes to bypass UORF2 and initiate translation at the *ATF4*-coding region. This mechanism shares key features with the yeast *GCN4* translation control, suggesting conservation from yeast to mammals. The study also examines the role of stem-loop structures and insertions between UORF1 and UORF2 in regulating ATF4 translation, providing insights into the timing and efficiency of translation reinitiation.The study investigates the mechanism by which ATF4 mRNA translation is regulated in response to eIF2 phosphorylation in mammalian cells. ATF4, a transcriptional regulator, is upregulated during cellular stress to activate genes involved in stress response. The 5' leader region of the *ATF4* mRNA contains two upstream ORFs (uORFs) that contribute differentially to ATF4 translation. UORF1 is a positive-acting element that facilitates ribosome scanning and reinitiation at downstream coding regions, while UORF2 is an inhibitory element that blocks ATF4 expression in non-stressed conditions. During stress, phosphorylation of eIF2 reduces eIF2-GTP levels, delaying reinitiation and allowing ribosomes to bypass UORF2 and initiate translation at the *ATF4*-coding region. This mechanism shares key features with the yeast *GCN4* translation control, suggesting conservation from yeast to mammals. The study also examines the role of stem-loop structures and insertions between UORF1 and UORF2 in regulating ATF4 translation, providing insights into the timing and efficiency of translation reinitiation.