Multiresistance in Gram-negative pathogens, particularly Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter spp. and the Enterobacteriaceae, is a significant problem in medicine today. While multiple mechanisms often contribute to multiresistance, a broadly distributed family of three-component multidrug efflux systems is an increasingly recognised determinant of both intrinsic and acquired multiresistance in these organisms. Homologues of these efflux systems are also readily identifiable in the genome sequences of a wide range of Gram-negative organisms, pathogens and non-pathogens alike, where they probably promote efflux-mediated resistance to multiple antimicrobials. Significantly, these systems often accommodate biocides, raising the spectre of biocide-mediated selection of multiresistance in Gram-negative pathogens. While there is some debate as to the natural function of these efflux systems, only some of which are inducible by their antimicrobial substrates, their contribution to resistance in a variety of pathogens nonetheless makes them reasonable targets for therapeutic intervention. Indeed, given the incredible chemical diversity of substrates accommodated by these efflux systems, it is likely that many novel or yet to be discovered antimicrobials will themselves be efflux substrates and, as such, efflux inhibitors may become an important component of Gram-negative antimicrobial therapy.