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Infections with Pseudomonas aeruginosa and Acinetobacter baumannii are of great concern for hospitalized patients, especially with multidrug-resistant strains. This review focuses on recent data that may help us to understand the emergence, spread, and persistence of antibiotic resistance, and summarizes the optional treatment feasible for these resistant bacteria.Multidrug-resistant P. aeruginosa and A. baumannii are increasingly causing nosocomial infections; multidrug-resistant clones are spreading into new geographic areas, and susceptible strains are acquiring resistance genes. New extended-spectrum β-lactamases and carbapenemases are emerging, leading to pan-resistant strains. Current studies focus on the effect of antibiotics on gene expression in P. aeruginosa biofilms and their contribution to resistance to therapy. Treatment options for multidrug-resistant P. aeruginosa and A. baumannii infections are limited in most cases to carbapenems. Sulbactam is a treatment option for pan-resistant A. baumannii, and or renewed use of an old drug, colistin, is being entertained for pan-resistant A. baumannii and P. aeruginosa. Immunotherapy is a promising new modality being explored. Prevention of emergence of resistance through combination therapy and pharmacokinetic strategies are studied.The emergence and spread of multidrug-resistant P. aeruginosa and A. baumannii and their genetic potential to carry and transfer diverse antibiotic resistance determinants pose a major threat in hospitals. The complex interplay of clonal spread, persistence, transfer of resistance elements, and cell–cell interaction contribute to the difficulty in treating infections caused by these multidrug-resistant strains. In the absence of new antibiotic agents, new modalities of treatment should be developed.