Pseudomonas aeruginosa is a common and often fatal pathogen in healthcare settings, known for its intrinsic resistance to many antimicrobials and the development of multidrug resistance. This review highlights the multifactorial mechanisms of resistance in P. aeruginosa, including chromosomal mutations and horizontal gene transfer. Key resistance mechanisms include upregulation of multidrug efflux systems, derepression of AmpC β-lactamases, alterations in outer membrane permeability, and changes in antimicrobial targets. Acquired resistance involves β-lactamases, particularly extended-spectrum β-lactamases and carbapenemases, aminoglycoside-modifying enzymes, and 16S rRNA methylases. The organism's ability to form biofilms and the presence of hypermutator strains further complicate treatment. With limited therapeutic options and increasing resistance, the emergence of untreatable P. aeruginosa infections is a growing concern. The review emphasizes the need for improved antimicrobial stewardship, resistance surveillance, and infection control measures to manage this challenging situation.Pseudomonas aeruginosa is a common and often fatal pathogen in healthcare settings, known for its intrinsic resistance to many antimicrobials and the development of multidrug resistance. This review highlights the multifactorial mechanisms of resistance in P. aeruginosa, including chromosomal mutations and horizontal gene transfer. Key resistance mechanisms include upregulation of multidrug efflux systems, derepression of AmpC β-lactamases, alterations in outer membrane permeability, and changes in antimicrobial targets. Acquired resistance involves β-lactamases, particularly extended-spectrum β-lactamases and carbapenemases, aminoglycoside-modifying enzymes, and 16S rRNA methylases. The organism's ability to form biofilms and the presence of hypermutator strains further complicate treatment. With limited therapeutic options and increasing resistance, the emergence of untreatable P. aeruginosa infections is a growing concern. The review emphasizes the need for improved antimicrobial stewardship, resistance surveillance, and infection control measures to manage this challenging situation.