Pseudomonas aeruginosa is a Gram-negative bacterium that causes severe and persistent infections in immunocompromised individuals and cystic fibrosis patients. Its ability to form biofilms and develop resistance to antibiotics makes it difficult to treat. Quorum sensing (QS), a cell-density-based communication system, plays a key role in regulating bacterial virulence and biofilm formation. The QS network of P. aeruginosa is organized in a multi-layered hierarchy with at least four interconnected signaling mechanisms: las, iqs, pqs, and rhl. Recent research shows that this network is highly adaptable and can respond to environmental stress cues, allowing the pathogen to flexibly control virulence gene expression. The las and rhl QS systems are central to P. aeruginosa's virulence. LasR and RhlR are key regulators that respond to autoinducers OdHDL and BHL, respectively. These systems regulate the expression of virulence factors such as elastase, pyocyanin, and rhamnolipids. The pqs system, which produces PQS, is also crucial for virulence and biofilm formation. PQS is structurally unique and is involved in various physiological processes. The recently identified IQS system integrates environmental stress cues with the QS network, highlighting the adaptability of P. aeruginosa's QS systems. The four QS systems interact closely, forming an intricate communication network. Environmental factors such as phosphate and iron depletion, oxygen deprivation, and host immune factors can modulate QS signaling. For example, phosphate starvation activates the pqs system and increases virulence. Iron deprivation can enhance the production of virulence factors like LasB elastase. Oxygen deprivation influences cyanide biosynthesis, which is a potent virulence factor. Host-derived immune factors, such as IFN-γ and dynorphin, can activate QS systems and enhance virulence. Understanding the QS regulatory mechanisms in P. aeruginosa is crucial for developing new therapeutic strategies. The adaptability of the QS network allows the pathogen to respond to environmental changes, making it a promising target for quorum sensing inhibitors (QSIs). However, the complexity of the QS systems and their interactions with environmental cues require further investigation to fully understand their role in bacterial virulence and biofilm formation. This review highlights the importance of QS in P. aeruginosa pathogenesis and the need for continued research to develop effective anti-QS therapeutics.Pseudomonas aeruginosa is a Gram-negative bacterium that causes severe and persistent infections in immunocompromised individuals and cystic fibrosis patients. Its ability to form biofilms and develop resistance to antibiotics makes it difficult to treat. Quorum sensing (QS), a cell-density-based communication system, plays a key role in regulating bacterial virulence and biofilm formation. The QS network of P. aeruginosa is organized in a multi-layered hierarchy with at least four interconnected signaling mechanisms: las, iqs, pqs, and rhl. Recent research shows that this network is highly adaptable and can respond to environmental stress cues, allowing the pathogen to flexibly control virulence gene expression. The las and rhl QS systems are central to P. aeruginosa's virulence. LasR and RhlR are key regulators that respond to autoinducers OdHDL and BHL, respectively. These systems regulate the expression of virulence factors such as elastase, pyocyanin, and rhamnolipids. The pqs system, which produces PQS, is also crucial for virulence and biofilm formation. PQS is structurally unique and is involved in various physiological processes. The recently identified IQS system integrates environmental stress cues with the QS network, highlighting the adaptability of P. aeruginosa's QS systems. The four QS systems interact closely, forming an intricate communication network. Environmental factors such as phosphate and iron depletion, oxygen deprivation, and host immune factors can modulate QS signaling. For example, phosphate starvation activates the pqs system and increases virulence. Iron deprivation can enhance the production of virulence factors like LasB elastase. Oxygen deprivation influences cyanide biosynthesis, which is a potent virulence factor. Host-derived immune factors, such as IFN-γ and dynorphin, can activate QS systems and enhance virulence. Understanding the QS regulatory mechanisms in P. aeruginosa is crucial for developing new therapeutic strategies. The adaptability of the QS network allows the pathogen to respond to environmental changes, making it a promising target for quorum sensing inhibitors (QSIs). However, the complexity of the QS systems and their interactions with environmental cues require further investigation to fully understand their role in bacterial virulence and biofilm formation. This review highlights the importance of QS in P. aeruginosa pathogenesis and the need for continued research to develop effective anti-QS therapeutics.