In the era of superbugs and antimicrobial resistance to conventional antibiotics, there is an urgent need for alternative drug delivery systems to optimize antimicrobial administration. Traditionally, routes of antimicrobial administration include oral, intravenous, intramuscular, intracerebroventricular, aerosol, rectal, and topical methods. However, more innovative drug delivery systems are required for the treatment of antimicrobial resistance at the cellular level. With recent advances, hefty research has been underway, including the use of nanotechnology and antimicrobial peptides in the fight against multi drug-resistant microorganisms (MDROs). Metal and polymer nanoparticles with or without surface functionalization and antimicrobial peptides act through different mechanisms of actions than conventional antibiotics. Some of these mechanisms of actions are included but are not limited to oxidative and non-oxidative stress, binding to the bacterial membrane, altering cell permeability and integrity, and activation of adaptive immune pathways. This chapter encompasses the cause and effect of multidrug resistance in addition to the nanoparticles, antimicrobial peptides, and gene editing techniques as an alternative or combinatorial antimicrobial combat mechanism for the 21st century.