Cadmium poisoning results in cell death. Although several intracellular pathways have been identified in this response, transport systems responsible for cadmium entry into cells remain poorly understood and controversial. Here, we analyzed the effects of several divalent cations on cadmium toxicity in different cell types. We found that zinc, previously reported as a protective agent against cadmium poisoning, is actually much less efficient than manganese. We show that manganese dramatically reduces cadmium intake, and that this is associated with the inhibition of our recently reported sustained activation of ERK, characteristic of cadmium intoxication. Finally, we show that this inhibition of cadmium entry and ERK-sustained activation perfectly correlates with a high cellular resistance to cadmium exposure. Our results, together with previously published data, support the idea that the yet to be characterized manganese transporter system(s) may be responsible for cadmium entry into cells. (c) 2006 Elsevier Inc. All rights reserved.