The mechanism of cellular cadmium (Cd) uptake has been poorly understood. Recently, we developed Cd-resistant cell lines from metallothionein null mouse cells and showed that the Cd resistance of these cells was conferred primarily by a reduced Cd accumulation. Surprisingly, the uptake rate of manganese (Mn) was also markedly reduced in Cd-resistant cells. Subsequent studies on the kinetics of Cd and Mn uptake by Cd-resistant and parental cells revealed that the Mn transport system with high affinity for Mn is used for cellular Cd uptake, and that this pathway is suppressed in Cd-resistant metallothionein null cells. This is the first indication that the transport system for Mn is used for Cd uptake in mammalian cells. Divalent metal transporter 1 (DMT1) is the only known mammalian transporter involved in the uptake of both Cd and Mn. However, the high-affinity Mn/Cd transport system we found seems to be distinct from DMT1 because of the difference in optimal pH and substrate specificity. On the other hand, various types of Mn transporters have been shown to play an important role in cellular Cd uptake in non-mammalian species such as yeast, plants and bacteria, suggesting the existence of Mn transporters other than DMT1 in mammals.