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Myxococcus xanthus has to cope with changes in its environment during growth and development. Among these factors, the concentration of copper is crucial due to the essential toxic effect of this metal, which forces the cells to maintain a tight homeostasis. The M. xanthus copper response is more complex than that in other bacteria, which is reflected by the different copper sensitivities of growing and developing cells. In the present study, the participation in copper homeostasis of six heavy metal efflux systems encoded in the M. xanthus genome has been examined. Three of these pumps exhibit the signature sequences in transmembrane domain 4 of the Cus systems (Cus1, Cus2, and Cus3), while the other three exhibit the motifs of the Czc systems (Czc1, Czc2, and Czc3). The Cus2 and Cus3 systems are inducible by copper and monovalent metals, functioning as the main copper efflux pumps, while the Cus1 …