Abstract: Due to the unique outer membrane barrier and their complex and diverse multidrug resistance mechanisms, the clinical resistance of Gram-negative bacteria is extremely severe, while the development of related new drugs has progressed slowly. This article systematically reviews representative anti-Gram-negative bacterial drugs that have been marketed in the past decade and those currently in clinical or preclinical research stages. It focuses on introducing drugs with novel targets/mechanisms of action and categorizes them based on intervention strategies targeting key stages of the Gram-negative bacterial life cycle, including: topoisomerase inhibition, protein synthesis disruption, protein transport obstruction, cell wall synthesis inhibition and damage, and bacterial cell division disruption. The content provides a comprehensive review of the structural information, mechanisms of action, antibacterial spectrum, clinical applications, as well as the applicational prospects and challenges of various classes of drugs.