Antimicrobial drug resistance has become a serious threat and it caused the death of 700,000 individuals in 2016. Gram-negative bacteria such as Acinetobacter, Pseudomonas, Enterobacter spp. Enterococcus faecium, Staphylococcus aureus, and Klebsiella pneumoniae are insensitive to antibiotics. E. faecium, S. aureus, K. pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. are called as “ESKAPE” group of pathogens which have multidrug resistance property. Multidrug-resistant (MDR) bacteria are involved in increased mortality and produce economic burden in the world. Bacteria escape the toxic action of antibiotics by increasing the efflux of antibiotics, inactivation of antibiotics through chemical modifications and modification of antibiotic targets. Bacteria use a genetic mechanism to avoid antibiotic effect through mutations in the gene(s) which are associated with antibiotic action and acquisition of resistance genes through horizontal gene transfer (HGT). The antibiotic resistance property in bacteria occurred through horizontal gene transfer such as transformation, transduction, and conjugation of plasmids or transposons, and mutations in the existing genes. Efflux pumps contribute antibiotic resistance at three levels such as intrinsic, acquired, and phenotypic. The human microbiome is considered as a reservoir of antibiotic resistance genes. Development of antibiotic resistance should be considered as an adaptive response in Darwinian’s principles of evolution. Therefore, understanding the molecular mechanisms and evolution of multidrug-resistant bacteria are need to be studied.