<p>Although carbapenems are still key drugs in the treatment of serious infections due to MDR Gram-negative bacteria, the high rate of emergence of carbapenem resistance is a serious global health concern. Carbapenemase production is well studied but so far efflux pumps play an important, yet underestimated role in the development of resistance. Efflux systems, especially those belonging to the resistance-nodulation-division family play a role in intrinsic and acquired resistance by actively expelling antibiotics and synergizing with other mechanisms like loss of porins and enzyme degradation, and biofilm formation. This review will offer a detailed and integrated perspective of efflux-mediated carbapenem resistance including the structure, regulation and genetic determinants of efflux activity. Special attention is given to the interplay of efflux pumps and co-resistance mechanisms which indicates that those mechanisms do not act as independent mechanisms but are embedded in a network of co-ordinated resistance. The review also covers new approaches to therapy such as efflux pump inhibitors and critically discusses the problems that hinder their use in the clinic. Importantly, this work reveals some important limitations with the current diagnostic methods, showing that efflux-mediated resistance is often underestimated due to a lack of standardized methods. Moreover, the drivers of efflux activity from an epidemiological and environmental perspective are discussed within a One Health context, such as antibiotic pressure and co-selection by heavy metals. This review aims to combine mechanistic, clinical and ecological aspects to present a more nuanced view of efflux-mediated resistance and highlights the need for better diagnostics, focused treatment strategies and overall antimicrobial stewardship to manage carbapenem resistance infections.</p>