Drug-resistant organisms may have acquired resistance to first-line antibiotics, thereby obligating the use of second-line agents and so this problem is a serious and pre-eminent public health concern in the 21st century. Evolutionary pressure caused by misuse and overuse of antibiotics has played a role in the development of multidrug-resistant varieties and the spread of resistance among bacterial species. Some pathogens, such as Pseudomonas aeruginosa, also dominate a high level of intrinsic resistance. This review discusses biochemical and genetic ways that bacteria use to become resistance against antimicrobial agents and authors interested to show the emergence of this global problem. Some new approaches to fight against our microscopic enemies should be discussed in this article.