Bacteria respond to metal pollution through sensors that control the uptake and the detoxification machineries. Specificity in metal recognition is therefore a prerequisite for triggering the appropriate response, particularly when facing a mixture of metals. In response to Cu + , the purple bacterium Rubrivivax gelatinosus induces the efflux Cu + -ATPase CopA by the Cu + regulator CopR. However, genetic analyses have suggested the presence of additional regulators. Here, we show that CadR, the Cd 2+ sensor, is involved in Cd 2+ and Cu + tolerance and demonstrate that CopR and CadR share common target genes. Interestingly, expression of the Cu + detoxification and efflux (CopI/CopA) system was induced by Cd 2+ and downregulated in the double mutant copRcadR -. This double mutant was more sensitive to low Cu + concentration than the single copR - mutant, and accumulation of coproporphyrin III pointed to a significantly decreased expression of CopA. Furthermore, analyses of Cd 2+ toxicity in the cadR -mutant suggested that although CopR is Cu + selective, CopR is involved in Cd 2+ response since the addition of Cu + alleviates Cd 2+ toxicity. Based on our current knowledge of metal transport across the inner membrane, Cd 2+ and Cu + do not share common efflux routes nor do they share common regulators. Nevertheless, the crosstalk between Cd 2+ and Cu + tolerance systems is demonstrated in the present study. The modulation of Cu + detoxification by a Cd 2+ regulator in vivo places emphasis on the relaxed selectivity, under elevated metal concentration, in MerR regulators.