The widespread occurrence of cadmium in the environment continues to pose a threat to human health despite attempts at limiting its technological uses. The biologically significant ionic form of cadmium, Cd2+, binds to many bio-molecules and these interactions underlie the toxicity mechanisms of cadmium. Some of the molecules specialized in the handling of alkaline earth (Mg2+, Ca2+) and transition metal ions (e.g. Zn2+, Cu2+/+, Fe3+/2+) should be particularly sensitive to the presence of Cd2+, because they enclose cationic sites to which the toxic metal can bind. The possible molecular targets of this kind for cadmium are considered herein. Whereas in vitro evidence for native cation replacement by Cd2+ in bio-molecules has been largely provided, the demonstration of such occurrences in vivo is scarce, with the notable exception of metallothionein. One reason might be that realistic low-level Cd2+ contaminations involve cellular concentrations far smaller than those of endogenous cations that usually saturate their binding sites. It is very likely that cadmium toxicity is most often mediated by biological systems amplifying the signals triggered by the presence of Cd2+. The interference of Cd2+ with redox sensitive systems acting at the transcriptional and post-transcriptional levels is instrumental in such processes. A better understanding of cadmium toxicity to tackle the environmental challenges lying ahead thus requires properly designed studies implementing biologically relevant cadmium concentrations on different cell types, improved knowledge of the homeostasis of essential metals, and use of these data in a theoretical framework integrating all cellular aspects of cadmium effects.