The development of resistance in micro-organisms against the antimicrobial agents is known as drug resistance, and this causes morbidity and mortality in humans and animals. Major contributing factors for the development of drug resistance are the overuse of antibiotics, inaccurate implementation, extended hospitalization, and unintended prescriptions. In this chapter, the authors described the functions of the most frequently prescribed and used drugs against bacteria and reported the mechanism leading to the development of resistance. Most common drugs include aminoglycosides, amphenicols, antifolates, β-lactams, glycopeptides, rifamycins, macrolides, quinolones, and tetracyclines which are extensively used against bacterial infections in humans and animals. Health authorities may manage and control the development of drug resistance through enforced legislation, strict ethical considerations, systematic management, reliable and efficient screening activities in any country and even at international levels. Up-to-date awareness, regarding the misuse of antibiotics and resulting in serious health concerns, among health workers and communities can also reduce the burdensome of drug resistance globally. With new information, technologies, and expertise, the challenges of drug-resistance can be handled urgently, and these resources can be the better ways for the development of next-generation drugs.