The article reviews the clinical significance and complex regulation of chromosomally encoded resistance mechanisms in *Pseudomonas aeruginosa*. *P. aeruginosa* is a versatile and opportunistic pathogen that has become increasingly resistant to antibiotics, posing significant therapeutic challenges. The review highlights the historical and clinical significance of *P. aeruginosa*, its widespread distribution, and its high rates of resistance to various antibiotics, particularly fluoroquinolones and β-lactams. The article discusses the increasing prevalence of multidrug-resistant strains and the impact of imported resistance mechanisms, such as β-lactamases and aminoglycoside-inactivating enzymes. It also delves into the chromosomally encoded resistance mechanisms, focusing on AmpC cephalosporinase, OprD outer membrane porin, and multidrug efflux pumps. The regulation of these mechanisms, including the role of AmpR, AmpD homologues, and PBP4, is explored in detail. The article emphasizes the complexity of these regulatory pathways and their implications for the treatment of *P. aeruginosa* infections.The article reviews the clinical significance and complex regulation of chromosomally encoded resistance mechanisms in *Pseudomonas aeruginosa*. *P. aeruginosa* is a versatile and opportunistic pathogen that has become increasingly resistant to antibiotics, posing significant therapeutic challenges. The review highlights the historical and clinical significance of *P. aeruginosa*, its widespread distribution, and its high rates of resistance to various antibiotics, particularly fluoroquinolones and β-lactams. The article discusses the increasing prevalence of multidrug-resistant strains and the impact of imported resistance mechanisms, such as β-lactamases and aminoglycoside-inactivating enzymes. It also delves into the chromosomally encoded resistance mechanisms, focusing on AmpC cephalosporinase, OprD outer membrane porin, and multidrug efflux pumps. The regulation of these mechanisms, including the role of AmpR, AmpD homologues, and PBP4, is explored in detail. The article emphasizes the complexity of these regulatory pathways and their implications for the treatment of *P. aeruginosa* infections.