The general stress response (GSR) is a widespread strategy used by bacteria to adapt to changing environments, triggered by multiple simultaneous stresses or during stationary phase. The alternative sigma factor RpoS is the central regulator of the GSR in *Escherichia coli* and is conserved in most γ-proteobacteria. RpoS is induced under conditions of nutrient deprivation and other stresses, primarily through the activation of its translation and inhibition of its proteolysis. This review covers recent advances in understanding how stresses lead to RpoS induction and defines RpoS-dependent genes and pathways. RpoS regulation involves multiple inputs, including transcriptional and translational controls. Transcriptional regulation of *rpoS* is influenced by factors such as ArcA, catabolite regulator protein (CRP), MqsA, and GadX. Translational regulation is primarily mediated by small regulatory RNAs (sRNAs) that interact with the 5' UTR of *rpoS* mRNA, altering its structure to allow ribosome binding and translation initiation. Other regulators, such as Hfq and RNase III, also influence RpoS translation. Proteolytic control plays a crucial role in RpoS regulation. RssB, an adaptor for RpoS degradation, binds to RpoS and delivers it to the ClpXP protease for degradation. However, under stress conditions, RssB activity is inhibited by Ira anti-adaptors (IraM, IraD, and IraP), which bind to RssB and prevent its interaction with RpoS. This stabilization of RpoS allows the cell to rapidly accumulate RpoS and initiate the GSR. The review also discusses the role of RpoS in various stress responses, including oxidative stress, acid resistance, and osmotic stress. It highlights the trade-off between growth and survival under stress conditions, where high RpoS levels can be disadvantageous. The regulation of RpoS in *E. coli* serves as a model for understanding the complex mechanisms of GSR regulation in bacteria.The general stress response (GSR) is a widespread strategy used by bacteria to adapt to changing environments, triggered by multiple simultaneous stresses or during stationary phase. The alternative sigma factor RpoS is the central regulator of the GSR in *Escherichia coli* and is conserved in most γ-proteobacteria. RpoS is induced under conditions of nutrient deprivation and other stresses, primarily through the activation of its translation and inhibition of its proteolysis. This review covers recent advances in understanding how stresses lead to RpoS induction and defines RpoS-dependent genes and pathways. RpoS regulation involves multiple inputs, including transcriptional and translational controls. Transcriptional regulation of *rpoS* is influenced by factors such as ArcA, catabolite regulator protein (CRP), MqsA, and GadX. Translational regulation is primarily mediated by small regulatory RNAs (sRNAs) that interact with the 5' UTR of *rpoS* mRNA, altering its structure to allow ribosome binding and translation initiation. Other regulators, such as Hfq and RNase III, also influence RpoS translation. Proteolytic control plays a crucial role in RpoS regulation. RssB, an adaptor for RpoS degradation, binds to RpoS and delivers it to the ClpXP protease for degradation. However, under stress conditions, RssB activity is inhibited by Ira anti-adaptors (IraM, IraD, and IraP), which bind to RssB and prevent its interaction with RpoS. This stabilization of RpoS allows the cell to rapidly accumulate RpoS and initiate the GSR. The review also discusses the role of RpoS in various stress responses, including oxidative stress, acid resistance, and osmotic stress. It highlights the trade-off between growth and survival under stress conditions, where high RpoS levels can be disadvantageous. The regulation of RpoS in *E. coli* serves as a model for understanding the complex mechanisms of GSR regulation in bacteria.