: The understanding of novel antibiotic resistance mechanisms is essential to develop strategies against antibiotic-resistant pathogens, which has become an urgent task due to the worldwide emergence of antibiotic resistance. : In this review, the authors summarize the recent progress on antibiotic resistance caused by lab-evolved bacteria and clinical multidrug-resistant bacterial pathogens from the proteomics perspective. : Proteomics provides a new platform for a comprehensive understanding of change in protein pathways that are engaged in antibiotics resistance, which is different from a genetic view that focuses on the role of an individual gene or protein. Further work is required to understand why and how the involved pathways are integrated for surviving antibiotic-mediated killing, to use other OMICs for better comprehension of antibiotic resistance mechanisms, and to develop reprogramming proteomics, which reverts an "antibiotic resistance proteome" to an "antibiotic sensitive or antibiotic sensitive-like" proteome, for the control of antibiotic-resistant pathogens.