The genus Xanthomonas contains plant pathogens exhibiting innate resistance to a range of antimicrobial agents. In other genera, multidrug resistance is mediated by a synergy between a low-permeability outer membrane and expression of a number of multidrug efflux systems. This report describes the isolation of a novel gene cluster xmeRSA from Xanthomonas strain IG-8 that mediates copper chloride resistance. Subsequent analysis of these genes showed that they were responsible for the high level of multiple resistance in this strain and were homologues of the sme system of Stenotrophomonas maltophilia. Knock-out mutants of this gene cluster indicate that these genes are required for the copper resistance phenotype of strain IG-8. Expression analysis using lacZ fusions indicates that the genes are regulated by copper and other antimicrobials. Bioinformatic analysis suggests that these genes were acquired by horizontal gene transfer.