Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged to be one of the world’s greatest health threats.  However, not only have recent decades shown a steady decline in the number of approved antimicrobial agents but a disappointing discovery also void.  The development of novel antibiotics to treat MDR Gram-negative bacteria has been stagnated over the last half century.  Though few compounds have shown activities in vitro, in animal models or even in clinical studies, the global antibiotic pipeline is not encouraging.  There are a plethora of unexpected challenges that may arise and cannot always be solved to cause promising drugs to fail.  This review intends to summarize recent research and development activities to meet the inevitable challenge in restricting the proliferation of MDR Gram-negative bacteria, with focus on compounds that have entered into clinical development stage.  In addition to new analogues of existing antibiotic molecules, attention is also directed to alternative strategies to develop antibacterial agents with novel mechanisms of action.