The biologic function of metallothionein (MT) has been a perplexing topic ever since the discovery of this protein. Many studies have suggested that MT plays a role in the homeostasis of essential metals such as zinc and copper, detoxification of toxic metals such as cadmium, and protection against oxidative stress. However, mechanistic insights into the actions of MT have not been adequately achieved. MT contains high levels of sulfur. The mutual affinity of sulfur and transition metals makes the binding of these metals to MT thermodynamically stable. Under physiologic conditions, zinc-MT is the predominant form of the metal-binding protein. The recognition of the redox regulation of zinc release from or binding to MT provides an alternate perspective on biologic function of MT. Oxidation of the thiolate cluster by a number of mild cellular oxidants causes zinc release and formation of MT-disulfide (or thionin if all metals are released from MT, but this is unlikely to occur in vivo), which have been demonstrated in vivo. Therefore, the thermodynamic stability of zinc binding makes MT an ideal zinc reservoir in vivo, and the redox regulation of zinc mobilization enables MT function in zinc homeostasis. MT-disulfide can be reduced by glutathione in the presence of selenium catalyst, restoring the capacity of the protein to bind zinc. This MT redox cycle may play a crucial role in MT biologic function. It may link to the homeostasis of essential metals, detoxification of toxic metals and protection against oxidative stress.