Rise in carbapenem-resistant Gram-negative bacterial infections, especially among immunocompromised patients in healthcare settings is an imminent threat as they are difficult to treat and result in a prolonged length of hospital stay, frequent treatment failures, increased economic burden on the patient and the nation, and a high rate of morbidity and mortality. Major carbapenemase-producing Gram-negative bacteria are carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Enterobacterales (CRE) such as Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., and others. These bacteria that contaminate health-care settings are the major causes of a wide range of hospital-associated infections including life-threatening septicemia, pneumonia, meningitis, bones and joint infections, and skin and soft-tissue infections. Carbapenems are regarded as last resort available antibiotics to treat multidrug-resistant Gram-negative bacterial infections that show resistance to most of the beta-lactam antibiotics in addition to fluoroquinolones, aminoglycosides, and trimethoprim-sulfamethoxazole. Emergence and spread of carbapenem-resistant Gram-negative pathogens such as CRE and CRAB is a matter of serious concern because of limited treatment options and grave consequences. The World Health Organization has given level one priority to these pathogens and the United States Centers of Disease Control and Prevention considers CRE and CRAB as one of the top five most priority pathogens of public health importance. Strict control measures by the government and public is critical to prevent emergence and dissemination of these dangerous pathogens. In this article, the authors have summarized the microbiological and epidemiological perspectives of CRE and CRAB with a special focus on diagnosis, prevention, and novel promising alternative treatment strategies.