Antimicrobial resistant organisms are associated with significant morbidity and mortality and have considerable burden on healthcare costs. Antimicrobial discovery was a major breakthrough in the field of infectious diseases and drug discovery until the unexpected rise of antimicrobial resistance which is now a public health threat. Imprudent use of antimicrobials have led to the emergence of microbial resistance strains and favoured microorganisms to successfully exploit every possible resistance mechanisms which includes, but not limited to, genetic mutations, gene pickup, horizontal gene transfer and heterologous expression. They have extended themselves to community settings highlighting the importance of reservoirs of antibiotic resistant microbes in environment. The antimicrobial therapeutic repertoire is also shrinking on a steady pace for present or impossible to treat multidrug resistant infections. This short review briefly discusses the different molecular mechanisms of antibiotic resistance which allow microbes to exhibit multidrug resistance trait. Prompt actions to limit the emergence and dissemination of multi-drug resistant superbugs through novel therapeutic approaches should be designed.