Mechanisms of bacterial resistance to fluoroquinolones fall into two principal categories, alterations in drug target enzymes and alterations that limit permeation of drug to the target, both resulting from chromosomal mutations. No specific resistance mechanisms of quinolone degradation or modification have been found. The target enzymes, DNA gyrase and topoisomerase IV are most commonly altered in domains near the enzyme active sites and in some cases reduced drug binding affinity has been demonstrated. Drug permeation is altered by mutations that increase expression of endogenous multidrug efflux pumps, alter outer membrane diffusion channels, or both. Recently a new plasmid-mediated resistance of an as yet undefined mechanism was found in clinical isolates of Klebsiella pneumoniae. Copyright 1999 Harcourt Publishers Ltd.