Quinolone resistance is induced by mutations on quinolone target enzymes such as gyrase and topo IV, and by mutations that prevent drug accumulation as a result of changes in outer membrane proteins and/or activation of drug-efflux pumps. Mutations on the target enzymes usually cause resistance to quinolones specifically, but mutations affecting drug accumulation confer resistance to multiple drugs. In most cases a single mutation does not cause high-level resistance to quinolones, but multiple mutations do. As the frequency of each mutation is about 10−8, multiple mutations hardly occur at the same time. Therefore, mutants with high-level resistance are likely to emerge in a stepwise fashion. The most important clinical point is that mutants, even with low levels of resistance, must not be selected upon quinolone treatment. In this context, we must remember that some quinolone-resistant mutants may be selected not only by quinolone derivatives but also by other kinds of antimicrobial agents. The future usefulness of quinolones as antimicrobials may depend on how carefully antimicrobial agents including quinolones are used clinically.