Multiple surveillance studies have demonstrated that resistance among prevalent pathogens is increasing at an alarming rate, leading to greater patient morbidity and mortality from nosocomial infections. Among Gram-positive organisms, the most important resistant pathogens are methicillin- (oxacillin-)resistant Staphylococcus aureus, beta-lactam-resistant and multidrug-resistant pneumococci, and vancomycin-resistant enterococci. Important causes of Gram-negative resistance include extended-spectrum beta-lactamases (ESBLs) in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis, high-level third-generation cephalosporin (Amp C) beta-lactamase resistance among Enterobacter species and Citrobacter freundii, and multidrug-resistance genes observed in Pseudomonas aeruginosa, Acinetobacter, and Stenotrophomonas maltophilia. In selecting an empiric treatment for a nosocomial infection, one should consider the prevalent resistance patterns. Antimicrobials used for the treatment of nosocomial infections should be effective against any likely resistant pathogens and should not further promote the development of resistance. Recent data suggest that because of ESBLs and high-level amp C beta-lactamase resistances, use of third-generation cephalosporins may be ineffective in many patients with nosocomial infections. In addition, use of these agents may allow overgrowth of inherently resistant enterococci. The role of fluoroquinolones in the empiric treatment of nosocomial infections is also being limited by new resistance patterns and increasing resistance levels. Available antimicrobials with good activity against many resistant pathogens include the carbapenems, piperacillin/tazobactam, and cefepime. In addition, several new agents with good activity against Gram-positive organisms are in development or have been recently released. Appropriate antimicrobial selection, surveillance systems, and effective infection-control procedures are key partners in limiting antimicrobial-resistant pathogen occurrence and spread.