This graphical abstract provides an overview of the major bacterial resistance mechanisms. The critical difference between the structure Gram-positive (Left) and Gram-negative bacteria (Right) lies in their cell wall composition. Bacteria confer resistance to antibiotics through four major mechanisms: (1) Antibiotic degrading enzymes directly inactivating the antibiotics by modifying their chemical structures; (2) Decrease the intracellular antibiotic concentrations by decreasing or loss of porins, to prevent the antibiotics to enter the intracellular space, and by actively pumping the antibiotics out to the extracellular space. (3) By modifying the target sites for antibiotics, the antibiotics can no longer disrupt the bacterial cell function. The antibiotic target sites can be in ribosomes, DNA replication enzymes, and cell wall precursors. (4) The target sites can be prevented from antibiotics access to antibiotics by for example, modifying the bacterial surface charge. LPS – Lipopolysaccharide. Display omitted •Antimicrobial resistance is a global crisis. It is causing millions of invasive infections each year.•We witnessed the rapid development of specific resistance to man-made antibiotics repeatedly.•Novel approach in the research and development of antimicrobials and drug delivery systems is urgently needed. Antimicrobial resistance is a normal evolutionary process for microorganisms. Antibiotics exerted accelerated selective pressure that hasten bacterial resistance through mutation, and acquisition external genes. These genes often carry multiple antibiotic resistant determinants allowing the recipient microbe an instant “super-bug” status. The extent of Antimicrobial Resistance (AMR) has reached a level of global crisis, existing antimicrobials are no long effective in treating infections caused by AMR pathogens. The great majority of clinically available antimicrobial agents are administered through oral and intra-venous routes. Overcoming antibacterial resistance by novel drug delivery approach offered new hopes, particularly in the treatment of AMR pathogens in sites less assessible through systemic circulation such as the lung and skin. In the current review, we will revisit the mechanism and incidence of important AMR pathogens. Finally, we will discuss novel drug delivery approaches including novel local antibiotic delivery systems, hybrid antibiotics, and nanoparticle-based antibiotic delivery systems.