Quinolones are a widely prescribed class of antibacterial drugs used to treat various bacterial infections. However, the widespread use of these drugs has led to an increasing number of quinolone-resistant bacterial strains. This review discusses the development of quinolones as antibacterials, the structure and function of gyrase and topoisomerase IV, and the mechanism of quinolone action against these enzymes. It also explores three mechanisms that reduce bacterial sensitivity to quinolones: target-mediated resistance, plasmid-mediated resistance, and chromosome-mediated resistance. Target-mediated resistance is the most common and clinically significant form, caused by mutations in gyrase and topoisomerase IV that weaken interactions between quinolones and these enzymes. Plasmid-mediated resistance results from extrachromosomal elements encoding proteins that disrupt quinolone-enzyme interactions, alter drug metabolism, or increase efflux. Chromosome-mediated resistance involves underexpression of porins or overexpression of efflux pumps, both of which decrease cellular concentrations of quinolones. Recent advancements in understanding how quinolones interact with gyrase and topoisomerase IV and how mutations cause resistance are discussed, along with potential approaches to designing new drugs that overcome resistance.Quinolones are a widely prescribed class of antibacterial drugs used to treat various bacterial infections. However, the widespread use of these drugs has led to an increasing number of quinolone-resistant bacterial strains. This review discusses the development of quinolones as antibacterials, the structure and function of gyrase and topoisomerase IV, and the mechanism of quinolone action against these enzymes. It also explores three mechanisms that reduce bacterial sensitivity to quinolones: target-mediated resistance, plasmid-mediated resistance, and chromosome-mediated resistance. Target-mediated resistance is the most common and clinically significant form, caused by mutations in gyrase and topoisomerase IV that weaken interactions between quinolones and these enzymes. Plasmid-mediated resistance results from extrachromosomal elements encoding proteins that disrupt quinolone-enzyme interactions, alter drug metabolism, or increase efflux. Chromosome-mediated resistance involves underexpression of porins or overexpression of efflux pumps, both of which decrease cellular concentrations of quinolones. Recent advancements in understanding how quinolones interact with gyrase and topoisomerase IV and how mutations cause resistance are discussed, along with potential approaches to designing new drugs that overcome resistance.