Antibiotic resistance has become a global public health priority. Polymyxins, a family of cationic polypeptide antibiotics, act as a final line of refuge against severe infections by Gram-negative pathogens with pan-drug resistance. Unfortunately, this last-resort antibiotic has been challenged by the emergence and global spread of mobilized colistin resistance determinants (mcr). Given the fact that it has triggered extensive concerns worldwide, we present here an updated view of MCR-like colistin resistance. These studies provide a basic framework for understanding the molecular epidemiology and resistance mechanism of MCR-like genes. However, further large-scale epidemiology and functional studies are urgently needed to better understand the biology of this clinically important antibiotic resistance. Although natural resistance to polymyxin is rare, emergence and global distribution of the plasmid-borne mobilized colistin resistance gene (mcr-1) raises a great challenge to public health. The discovery of MCR-1 and its variants represents a new mechanism for transferable resistance to polymyxin, a ‘last-resort’ refuge against superbugs with carbapenem resistance. It seems likely that understanding the epidemiology of MCR-like genetic determinants will allow us to formulate efficient strategies (intervention and even elimination) to prevent acquired colistin resistance. Structural dissection of full-length MCR-like enzymes provides clues for screening or designing small-molecule drugs targeting catalytic activity and phosphatidylethanolamine (PE) substrate-binding of the MCR-like enzyme to bypass colistin resistance.