Cadmium is not an essential element for life. It is geologically marginal but anthropogenic activities have contributed significantly to its dispersion in the environment and to cadmium exposure of living species. The natural speciation of the divalent cation Cd2+ is dominated by its high propensity to bind to sulfur ligands, but Cd2+ may also occupy sites providing imidazole and carboxylate ligands. It binds to cell walls by passive adsorption (bio-sorption) and it may interact with surface receptors. Cellular uptake can occur by ion mimicry through a variety of transporters of essential divalent cations, but not always. Once inside cells, Cd2+ preferentially binds to thiol-rich molecules. It can accumulate in intracellular vesicles. It may also be transported over long distances within multicellular organisms and be trapped in locations devoid of efficient excretion systems. These locations include the renal cortex of animals and the leaves of hyper-accumulating plants. No specific regulatory mechanism monitors Cd2+ cellular concentrations. Thiol recruitment by cadmium is a major interference mechanism with many signalling pathways that rely on thiolate-disulfide equilibria and other redox-related processes. Cadmium thus compromises the antioxidant intracellular response that relies heavily on molecules with reactive thiolates. These biochemical features dominate cadmium toxicity, which is complex because of the diversity of the biological targets and the consequent pleiotropic effects. This chapter compares the cadmium-handling systems known throughout phylogeny and highlights the basic principles underlying the impact of cadmium in biology.