Pseudomonas aeruginosa is an important nosocomial pathogen that presents a difficult therapeutic challenge. Although P. aeruginosa has been shown to acquire resistance mechanisms encoded on plasmids, this pathogen comes armed with multiple chromosomally-encoded mechanisms of resistance that can provide impressive intrinsic resistance, as well as the potential to mutate to high-level multi-drug resistance. Recent analysis of the sequenced genome of P. aeruginosa PAO1 suggested that we have just started to unlock the resistance potential of this pathogen. One of the most serious threats to the usefulness of beta-lactams against P. aeruginosa is the chromosomal AmpC cephalosporinase. When AmpC production increases through mutational events, overproduction of this cephalosporinase provides high-level resistance to all beta-lactams except the carbapenems. Carbapenem resistance typically requires down-regulation of the outer membrane protein (OprD), which serves as the primary route of entry for carbapenems. Perhaps the most threatening of the resistance mechanisms encoded on the P. aeruginosa chromosome are the multi-drug efflux pumps. These pumps have the ability to extrude multiple classes of antibiotics from the periplasmic space, as well as the cytoplasm. Natural expression of efflux pumps in 'wild-type' cells plays an important role in the relatively decreased susceptibility of P. aeruginosa to antibiotics. However, the greatest therapeutic problems occur when these pumps are overproduced in mutants and high-level, multi-drug resistance develops. Although the development of infections with highly resistant strains of P. aeruginosa can present serious therapeutic challenges, the most troublesome threat associated with the chromosomally-encoded resistance mechanisms is the potential for high-level resistance to emerge during the course of therapy. When resistance emerges during therapy, clinical failure can occur and the therapeutic options for second-line therapy can become severely limited. Unfortunately, the emergence of resistance during therapy is not a rare event with P. aeruginosa and these three resistance mechanisms. Therefore, clinicians must be mindful of this threat when choosing an appropriate therapy, and usually appropriate therapy includes a combination of drugs. Since the standard combination of an aminoglycoside and a beta-lactam has been shown to be ineffective in preventing the emergence of some resistance problems, the search for more effective combinations must be a priority.