Gram-negative bacterial (GNB) infections represent a worldwide serious public health challenge, especially with the increased global spread of carbapenem resistance (CR) among these pathogens. There are different forms of CR including, intrinsic and acquired mechanisms, one of the most significant of which is carbapenemase production. In the last decade, the widespread plasmid-mediated carbapenemase production, on top of the chromosomally encoded carbapenemases-already abundant since the 1990s-further complicated the situation and necessitated urgent intervention to further understand and tackle this issue. In this review, the phenotypic and genotypic methods for the detection of different types of carbapenemase have been discussed. Also, the different control measures and strategies that should be applied in an attempt to control the massive spread of GNB infections especially in healthcare facilities, have been elaborated on in this article. The challenges of GNB-associated infection in terms of the emergence of resistance to carbapenems, the last line of defense against GNB, and the continuing spread of this resistance left us with almost no options for treatment as well as their complication on the host. On the other hand, we explore the various opportunities for their control such as the development of new classes of antimicrobials and the structural modification of existing ones. It is also inevitable to explore novel treatment options including the association of antimicrobial agents with non-antimicrobials, inhibition of quorum sensing, bacteriophage therapy, photodynamic therapy, and monoclonal antibodies for treatment and prevention.