The continuous emergence of drug-resistant bacteria has become a severe threat to the public health. Therefore, the discovery of novel antibacterial mechanisms to combat this jeopardized problem is urgently needed. In the past decades, plenty of new antibacterial modes of action have been discovered continuously, based on which many promising scaffolds have been designed and synthesized. In particular, cationic amphiphilic small-molecules open a door to the new mode of action of bactericidal agents by depolarizing and disturbing the bacteria membrane. The cationic amphiphilic are characterized by high efficacy, resistant-proof, wide-spectrum, and high selectivity toward bacteria. In this review, we summarized recent advances in the discovery of membrane-active small-molecules and their structure-activity relationships (SARs), hoping to provide an evidence for future research and development of new antibacterial agents with new mechanism.