An understanding of the epidemiology of multi-drug-resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa infections is necessary in order to develop strategies to curtail their spread. For this purpose, the evidence linking the isolation of MDR A. baumannii and P. aeruginosa with specific risk factors was evaluated. PubMed was searched for the 20-year period from September 1985 to September 2005, and eligible studies were considered to be those that: (1) linked the isolation of A. baumannii and P. aeruginosa with specific risk factors; (2) described the characteristics of the affected patients in detail; and (3) provided data on the antibiotic resistance profile of the isolated micro-organisms. Fifty-five studies were found referring to A. baumannii (28 with case–control methodology and 27 outbreak investigations without case–control methodology), and 42 studies were found referring to P. aeruginosa (25 with case–control methodology and 17 outbreak investigations without case–control methodology). Although heterogeneous study designs and investigated risk factors limited this analysis, it was concluded that acquisition and spread of these micro-organisms appear to be related to a large number of variables. Among the most important were deficiencies in the implementation of infection control guidelines and the use of broad-spectrum antibiotics. Use of carbapenems and third-generation cephalosporins appear to be related to the development of an MDR phenotype by A. baumannii, while carbapenems and fluoroquinolones are implicated in MDR P. aeruginosa. The diversity of risk factors associated with the development of MDR A. baumannii and P. aeruginosa suggests that a separate outbreak investigation should be performed in each hospital setting. The development of innovative control strategies is needed in order to limit the spread of these pathogens.