The increasing resistance of the disease-causing pathogens to antimicrobial drugs is a public health concern and a socio-economic burden. The emergence of multi-drug resistant strains has made it harder to treat and combat infectious diseases with available conventional antibiotics. There are currently few effective therapeutic regimens for the successful prevention of infections caused by drug-resistant microbes. Various alternative strategies used in the recent past to decrease and limit antibiotic resistance in pathogens include bacteriophages, vaccines, anti-biofilm peptides, and antimicrobial peptides. However, in this review, we focus on the novel and robust molecular approach of antisense RNA (asRNA) technology and the clustered regulatory interspaced short palindromic repeat (CRISPR)-based antibiotic therapy, which can be exploited to selectively eradicate the drug-resistant bacterial strain in a sequence-specific fashion establishing opportunities in the treatment of multi-drug resistant related infections.