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.