Antimicrobial resistance (AMR) is a growing threat tohuman and animal health, reducing the ability to treat bacterial infections and consequentlythe risk of morbidity and mortality caused by re-sistant bacteria. The World Health Organization (WHO)has predicted 10 million deaths by 2050 due to infectious diseases. A considerable increase in the number of pathogens harbor multidrug resistance genes, seemed to be arising from the extensive useof antimicrobial agents for medical issues particularly in food-producing animals, along with the many pathways of their release into the environment. The emergence of multidrug-resistant (MDR)microorganisms has threatened the longstandinguse of antibi-otics,which weregloballyused to save millions of lives.The evolution and spread of AMR have a great adverse impact on human beings. Naturally, bacteriahave the genetic abilityto acquire and spreadre-sistance to therapeutic agents. Therefore, the major challenge has been to limit the extensiveand the inappropriate overuseof antibiotics, in addition tofinding new drugs either from synthetic or natural origin to counter microbial resistance by acting on the specific target responsible for MDR. To overcome the crisis of antimicrobial drug resistance,WHO has issued several guidelines on the use of antimicrobial agents, such as preserving antibiotics that are important for human health and preventing their usage in agriculture.Several therapeutic approaches like vaccines, antimicrobial peptides, bacteriophages, and nanotechnology, along with phytochemicals and herbal medicines, are applied in vitroand in vivoexper-iments and are supposed to be suitable candidates for antimicrobials to combat the rapidly evolving AMR. In this review, we will discuss the causes of this resistance, types, its spread between ecosystems, super-resistance associated with superbugs like E. coli, and thepossible therapeutic approaches against MDR pathogens.