The tripartite efflux pump CmeABC is the most important efflux system in Campylobacter spp. that confers multidrug resistance. Yao, Shen et al. report the identification of a CmeABC variant that exhibits enhanced efflux function. This variant, termed resistance-enhancing CmeABC (RE-CmeABC), was more potent in excreting several antibiotics, including florfenicol and fluoroquinolones, which is probably because of the overexpression and sequence variation of RE-CmeABC. Structural modelling suggested that altered antibiotic-binding kinetics enhance the function of the inner membrane transporter CmeB. Moreover, genotyping analysis implied that clonal expansion and horizontal transmission were involved in the spread of this variant. Thus, the acquisition of a functionally enhanced efflux pump provides an efficient means for bacterial adaptation to selective pressure by antibiotics.