This review discusses recent advances in developing novel therapeutic strategies against multidrug-resistant (MDR) Pseudomonas aeruginosa, a major cause of severe healthcare-associated infections. P. aeruginosa is an opportunistic pathogen that causes various infections, including those in cystic fibrosis, ventilator-associated pneumonia, and burn injuries. Due to its large genome and complex molecular mechanisms, it exhibits high antimicrobial resistance. The review focuses on recent developments in antimicrobial agents and inhibitors targeting lipopolysaccharide (LPS) and porin proteins, as well as emerging treatment strategies such as phages, vaccines, and nanoparticles. Key mechanisms of antimicrobial resistance in P. aeruginosa include low outer membrane (OM) permeability, drug-resistant efflux pumps, and biofilm formation. LPS plays a critical role in OM permeability, and its biosynthesis is a target for new antibiotics. LpxC, a zinc-dependent enzyme involved in lipid A biosynthesis, is a promising target for antimicrobial agents. Several LpxC inhibitors have been developed, with some showing significant activity against MDR P. aeruginosa. However, few have reached clinical trials due to limited efficacy and toxicity. LPS modification, such as the addition of positively charged moieties like phosphoethanolamine (pEtN) and 4-amino-4-deoxy-L-arabinose (L-Ara4N), reduces colistin affinity. Colistin resistance in P. aeruginosa can be chromosomal or plasmid-mediated, with the mcr-1 gene being a key factor. LPS transport is another target, with MsbA and Lpt proteins playing essential roles. Inhibitors of these proteins have shown promise in reducing P. aeruginosa growth. Porins, such as OprD and OprF, are critical for OM permeability and are targets for vaccine development. Vaccines targeting OprF and OprI have shown potential in clinical trials. Phage therapy is also being explored as an alternative to traditional antibiotics, with several clinical trials underway. Nanoparticles and mRNA-based vaccines are emerging as promising new strategies for treating MDR P. aeruginosa. Despite these advances, challenges remain in combating MDR P. aeruginosa, including the rapid evolution of resistance and the need for new antibiotics. The review highlights the importance of developing novel therapeutic strategies to address the growing threat of antimicrobial resistance.This review discusses recent advances in developing novel therapeutic strategies against multidrug-resistant (MDR) Pseudomonas aeruginosa, a major cause of severe healthcare-associated infections. P. aeruginosa is an opportunistic pathogen that causes various infections, including those in cystic fibrosis, ventilator-associated pneumonia, and burn injuries. Due to its large genome and complex molecular mechanisms, it exhibits high antimicrobial resistance. The review focuses on recent developments in antimicrobial agents and inhibitors targeting lipopolysaccharide (LPS) and porin proteins, as well as emerging treatment strategies such as phages, vaccines, and nanoparticles. Key mechanisms of antimicrobial resistance in P. aeruginosa include low outer membrane (OM) permeability, drug-resistant efflux pumps, and biofilm formation. LPS plays a critical role in OM permeability, and its biosynthesis is a target for new antibiotics. LpxC, a zinc-dependent enzyme involved in lipid A biosynthesis, is a promising target for antimicrobial agents. Several LpxC inhibitors have been developed, with some showing significant activity against MDR P. aeruginosa. However, few have reached clinical trials due to limited efficacy and toxicity. LPS modification, such as the addition of positively charged moieties like phosphoethanolamine (pEtN) and 4-amino-4-deoxy-L-arabinose (L-Ara4N), reduces colistin affinity. Colistin resistance in P. aeruginosa can be chromosomal or plasmid-mediated, with the mcr-1 gene being a key factor. LPS transport is another target, with MsbA and Lpt proteins playing essential roles. Inhibitors of these proteins have shown promise in reducing P. aeruginosa growth. Porins, such as OprD and OprF, are critical for OM permeability and are targets for vaccine development. Vaccines targeting OprF and OprI have shown potential in clinical trials. Phage therapy is also being explored as an alternative to traditional antibiotics, with several clinical trials underway. Nanoparticles and mRNA-based vaccines are emerging as promising new strategies for treating MDR P. aeruginosa. Despite these advances, challenges remain in combating MDR P. aeruginosa, including the rapid evolution of resistance and the need for new antibiotics. The review highlights the importance of developing novel therapeutic strategies to address the growing threat of antimicrobial resistance.