The treatment of infections caused by multidrug-resistant Gram-negative bacteria is challenging given the limited options for effective therapy. Combination therapy has garnered great interest recently, with the goals of ensuring appropriate therapy with at least one active agent, and achieving synergistic activity among the anti-microbials used. In this review, we evaluate the data supporting the use of combination therapy against Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, Acinetobacter species and Stenotrophomonas maltophilia. Various regimens have been tried with promising results; however, the data are mostly derived from in vitro synergy studies. While these reports suggest an advantage of combination therapy over monotherapy, clinical data are scarce, and are comprised of retrospective and a few prospective observational studies. Well-designed randomized trials are needed to better elucidate the efficacy of the various combination regimens. Until then, this review offers a critical appraisal of the published literature and provides recommendations based on the available evidence.