Carbapenems are usually regarded as the last treatment option for serious infections caused by Gram-negative and Gram-positive microorganisms. Although they are stable to hydrolysis by most β- lactamases, their usage as the last resort antbiotics was seriously compromised by the appearance of carbapenem-hydrolyzing enzymes called carbapenemases. These enzymes are produced mostly by Enterobacteriaceae and Gram-negative nonfermentative bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. True carbapenemases belonging to Ambler molecular classes A, B, and D are often encoded by genes embedded in mobile genetic elements like plasmids, integrons, and transposons, which often harbor multiple resistance determinants limiting further the treatment options. At present, large number of nosocomial and community-acquired infections caused by worldwide spread of carbapenem-resistant Gram-negative bacteria have become a major public health problem. Although polymyxins remain active, in vitro reports of benefits of combination schemes favor this strategy against carbapenemase- producing Gram-negative bacilli.