Pseudomonas aeruginosa is a common nosocomial pathogen that causes severe infections with high mortality rates. It is inherently resistant to many antimicrobials and can develop multidrug resistance, complicating treatment. Resistance mechanisms include chromosomal mutations and horizontal gene transfer, leading to resistance to various antimicrobial classes. Key resistance mechanisms involve β-lactamases, such as extended-spectrum β-lactamases (ESBLs) and carbapenemases, which hydrolyze β-lactam antibiotics. Additionally, efflux systems like MexAB-OprM and MexXY-OprM contribute to resistance by expelling antimicrobials. Biofilms and hypermutator strains also enhance resistance. Aminoglycoside resistance is mediated by modifying enzymes and efflux systems. Polymyxins, like colistin, are increasingly used against multidrug-resistant strains, though resistance is emerging. Biofilm formation increases antimicrobial resistance, and hypermutability in P. aeruginosa leads to higher resistance development. With limited new antibiotics and increasing resistance, untreatable P. aeruginosa infections may become more common. Efforts to develop new therapies and improve antimicrobial stewardship are crucial to combat this growing threat.Pseudomonas aeruginosa is a common nosocomial pathogen that causes severe infections with high mortality rates. It is inherently resistant to many antimicrobials and can develop multidrug resistance, complicating treatment. Resistance mechanisms include chromosomal mutations and horizontal gene transfer, leading to resistance to various antimicrobial classes. Key resistance mechanisms involve β-lactamases, such as extended-spectrum β-lactamases (ESBLs) and carbapenemases, which hydrolyze β-lactam antibiotics. Additionally, efflux systems like MexAB-OprM and MexXY-OprM contribute to resistance by expelling antimicrobials. Biofilms and hypermutator strains also enhance resistance. Aminoglycoside resistance is mediated by modifying enzymes and efflux systems. Polymyxins, like colistin, are increasingly used against multidrug-resistant strains, though resistance is emerging. Biofilm formation increases antimicrobial resistance, and hypermutability in P. aeruginosa leads to higher resistance development. With limited new antibiotics and increasing resistance, untreatable P. aeruginosa infections may become more common. Efforts to develop new therapies and improve antimicrobial stewardship are crucial to combat this growing threat.