Stenotrophomonas maltophilia has emerged as an important nosocomial pathogen capable of causing respiratory, bloodstream, and urinary infections. The treatment of nosocomial infections by S. maltophilia is difficult, as this pathogen shows high levels of intrinsic or acquired resistance to different antimicrobial agents, drastically reducing the antibiotic options available for treatment. Intrinsic resistance may be due to reduced outer membrane permeability or to the multidrug efflux pumps. However, specific mechanisms of resistance such as aminoglycoside-modifying enzymes or the heterogeneous production of metallo-beta-lactamase have contributed to the multidrug-resistant phenotype displayed by this pathogen. Moreover, the lack of standardized susceptibility tests and their interpretative criteria hinder the choice of an adequate antibiotic treatment. Recommendations for the treatment of infections by S. maltophilia are based on in vitro studies, certain nonrandomized clinical trials, and anecdotal experience. Trimethoprim-sulfamethoxazole remains the drug of choice, although in vitro studies indicate that ticarcillin-clavulanic acid, minocycline, some of the new fluoroquinolones, and tigecycline may be useful agents. This review describes the main resistance mechanisms, the in vitro susceptibility profile, and treatment options for S. maltophilia infections.