The clustered regularly interspaced short palindromic repeat (CRISPR)-Caspase (Cas) system acts as a natural defense of bacteria against invasion by mobile genetic elements, such as plasmids, transposons, and bacteriophages. The review discusses the different classes and types of CRISPR-Cas systems in terms of principles of their action, limitations, and future perspectives. Also, the role of the CRISPR-Cas system as a new arsenal in fighting multidrug-resistant pathogens and clinically relevant pathogenic viruses and up-to-date clinical trials have been discussed and highlighted. Moreover, the utilization mode, regulation, and the link of CRISPR-Cas to quorum sensing for targeting cell chromosome or antimicrobial-resistant gene(s) of some clinically relevant pathogens, including Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa have been discussed. The information provided in this review can act as a platform for researchers for the future use of the CRISPR-Cas system as a smart antimicrobial agent for combating infections caused by life-threatening pathogens, particularly those with limited therapeutic options.