In order to produce their cytotoxic effect, quinolones must enter the cell through the bacterial membrane to reach their target, DNA-gyrase or topoisomerase IV, and induce cell death. The mechanisms of resistance to fluoroquinolones include: those mediated by gene mutations codifying for DNA gyrase and topoisomerase IV and leading to QRDR; those characterized by changes in the permeability of the outer membrane which decrease intracellular penetration of the drug; and those caused by active endogenous carriers responsible for drug efflux. These resistance mechanisms can occur alone or in combination; in fact, it is believed that high resistance levels to quinolones in vivo are associated with simultaneous mechanisms. This article reviews such resistance mechanisms and establishes, when possible, their relation to the structure of quinolones.