Abstract: The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins system (Cas), as a highly efficient gene-editing tool, offers promising approaches to directly kill pathogens or eradicate drug resistance genes to restore bacterial susceptibility by targeting essential genes of bacteria, and it gradually becomes a leading edge of development of antidrug-resistant technique. In recent years, CRISPR-based technologies have demonstrated significant potential in targeted bacterial eradication, clearance of drug-resistant plasmids, and delivery via prokaryotic vectors such as bacteriophages. Nevertheless, the translations of the technologies to clinical practices remain hindered by several technological difficulties, including off-target effects, dependence on specific protospacer adjacent motifs(PAMs), suboptimal delivery efficiency, and the excessive volume of Cas proteins. Therefore, current research should focus on engineering transformation of the CRISPR system, including boosting activity and specificity through directed evolution, optimizing structure function of Cas based on rational design, and achieving intelligent redesign and miniaturization in virtue of protein language models. This review also highlights the prospective advantages and future trajectories of the CRISPR-based technologies in precise elimination of drug-resistant bacteria and management of clinical infections.