Although the vast majority of antibiotic resistance mutations confer a fitness cost in the absence of antibiotic selective pressure, a study by Baker et al. now challenges this dogma. Salmonella enterica subsp. enterica serovar Typhi strains that have fluoroquinolone resistance mutations in the DNA gyrase gene gyrA, the topoisomerase gene parC or in both genes were competitively grown with an isogenic fluoroquinolone-sensitive wild-type strain in the absence of antibiotics. Most of the resistant mutants out-competed the wild-type strain, and interestingly, strains that had two mutations showed higher fitness than single mutants, which suggests that resistance mutations epistatically interact to increase fitness. These findings imply that resistant S. Typhi mutants would persist even after drug withdrawal and that antibiotic exposure is not the only factor that contributes to the maintenance of resistant strains.