Pseudomonas aeruginosa is one of the leading gram-negative organisms associated with nosocomial infections. The increasing frequency of multi-drug-resistant Pseudomonas aeruginosa (MDRPA) strains is concerning as efficacious antimicrobial options are severely limited. By searching MEDLINE from January 1966-February 2005 and relevant journals for abstracts, we reviewed the frequency, risk factors, and patient outcomes of MDRPA nosocomial infections in critically ill patients, determined the available antimicrobial therapies, and then provided recommendations for clinicians. The definition of MDRPA was established as isolates intermediate or resistant to at least three drugs in the following classes: beta-lactams, carbapenems, aminoglycosides, and fluoroquinolones. Reported rates of MDRPA varied from 0.6-32% according to geographic location and type of surveillance study. Risk factors for MDRPA infection included prolonged hospitalization, exposure to antimicrobial therapy, and immunocompromised states such as human immunodeficiency virus infection. Emergence of MDRPA isolates during therapy was reported in 27-72% of patients with initially susceptible P. aeruginosa isolates. Patients with severe MDRPA infections should be treated with combination therapy, consisting of an antipseudomonal beta-lactam with an aminoglycoside or fluoroquinolone rather than aminoglycoside and fluoroquinolone combinations, to provide adequate therapy and improve patient outcomes. Synergy has been observed when resistant antipseudomonal drugs were combined in vitro against MDRPA with successful clinical application reported in two centers. Colistin with adjunctive therapy, such as a beta-lactam or rifampin, may be a useful agent in MDRPA when antimicrobial options are limited, but patients should be monitored closely for toxicities associated with this agent. Standardization of terminology for MDRPA isolates is needed for consistency and comparability of surveillance and institutional reports. Clinical studies are needed to identify risk factors for MDRPA development and to determine the economic impact of these infections, as well as to determine the most efficacious antimicrobial regimens and duration of therapy to maximize outcomes in the treatment of MDRPA infections.