Imipenem (IMI)/cilastatin/relebactam (REL) (I/R) is a novel β-lactam/β-lactamase inhibitor combination with expanded microbiologic activity against carbapenem-resistant non- (CR-NME) and difficult-to-treat (DTR) Pseudomonas aeruginosa. Relebactam, a bicyclic diazabicyclooctane, has no direct antimicrobial activity but provides reliable inhibition of many Ambler class A and class C enzymes. It is currently approved for the treatment of adult patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) and those with complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) when limited or no alternative treatments are available. Given the number of recently approved β-lactams with expanded activity against highly resistant Gram-negative pathogens, this review summarizes the published literature on I/R, with a focus on its similar and distinguishing characteristics relative to those of other recently approved agents. Overall, available data support its use for the treatment of patients with HABP/VABP, cUTI, and cIAI due to CR-NME and DTR P. aeruginosa. Data indicate that I/R retains some activity against CR-NME and DTR P. aeruginosa isolates that are resistant to the newer β-lactams and vice versa, suggesting that susceptibility testing be performed for all the newer agents to determine optimal treatment options for patients with CR-NME and DTR P. aeruginosa infections. Further comparative PK/PD and clinical studies are warranted to determine the optimal role of I/R, alone and in combination, for the treatment of patients with highly resistant Gram-negative infections. Until further data are available, I/R is a potential treatment for patients with CR-NME and DTR P. aeruginosa infections when the benefits outweigh the risks.