Low concentrations of essential trace metals such as zinc (Zn) were recently shown to strongly modulate cadmium (Cd) uptake in the freshwater alga Chlamydomonas reinhardtii. Here we studied the mechanisms of Cd and Zn acquisition by this alga, using metal uptake kinetics experiments. Cadmium uptake rates fitted a three transport site model characterized by the affinity constants K(Cd–1)(Cd) = 10(5.0), K(Cd–2)(Cd) = 10(7.6), and K(Cd–3)(Cd) = 10(8.8). Similar uptake kinetics were obtained for Zn with K(Zn–1)(Zn) = 10(5.0), K(Zn–2)(Zn) = 10(7.4), and K(Zn–3)(Zn) > 10(9). Competitive binding experiments suggest that Zn and Cd share the same three transport systems. The capacities of the transport systems were modulated by as much as 10-fold following preacclimation to high or low Zn(2+) and Cd(2+) concentrations. We conclude that the strong protective effect of Zn on Cd accumulation is mainly due to the reduction of the maximal uptake rate of the high-affinity Zn–2 (or Cd–2) transport system. A biotic ligand model was developed to incorporate the effects of both chemical speciation and physiological regulation of Cd transport systems. The model successfully predicts the experimentally measured steady-state Cd content of C. reinhardtii in the presence of low or high [Zn(2+)].