Pseudomonas aeruginosa continues to be a major cause of infections in Western society, in part because of its high intrinsic resistance to antibiotics. It has been demonstrated that this intrinsic resistance arises from the combination of unusually restricted outer-membrane permeability and secondary resistance mechanisms such as energy-dependent multidrug efflux and chromosomally encoded periplasmic beta-lactamase. Given this high level of natural resistance, mutational resistance to most classes of antibiotics can readily arise. In this review we summarize new insights into the mechanisms of resistance, and describe therapeutic approaches that can be used in the face of this continuing resistance threat, as well as new approaches that are being developed to combat resistance. Copyright 2000 Harcourt Publishers Ltd.