Abstract: OBJECTIVE The clinical isolates of multidrug-resistant or carbapenem-resistant Enterobacteriaceae (CRE) show an increasing trend year by year, which poses a severe challenge to clinical use of antibiotics. With the decline of sensitivity to most of the commonly used antibiotics, tigecycline has played a crucial role in treatment of multidrug-resistant Enterobacteriaceae infections and has been regarded as one of the last optional antibiotics for the treatment of carbapenem-resistant Klebsiella pneumoniae. However, in recent years, the clinical isolates of CRE showed varying degree of resistance against tigecycline, and correlational studies revealed that the drug resistance mechanisms were associated with upregulated expressions of various regulatory pathways of efflux pumps, and even the related drug resistance genes might be transmitted via plasmid mediation. In terms of the perspective of "One World, One Health", it is urgent to comprehensively clarify the multiple cross resistance mechanisms of tigecycline and take precise measures to monitor and curb the further spread of its drug resistance.