Metallothionein (MT) is a ubiquitous, cysteine-rich, metal-binding protein. MT synthesis is induced by various stimuli such as cadmium, mercury, zinc, oxidative stress, glucocorticoid, and anticancer agents. Recently, transgenic mice with loss-of-function mutations in the MT-I/-II genes were established. It has been assumed that MT plays a role in the detoxification of heavy metals. In recent studies using MT-null mice, the ability of MT to protect against cadmium-induced renal, liver and bone injuries has been confirmed. Moreover, MT is also capable of scavenging oxygen free radicals. MT is involved in the protection of tissues against various forms of oxidative injury, including radiation, lipid peroxidation, oxidative stress caused by anticancer drugs, and conditions of hyperoxia. However, MT still lacks an established biological function. Unexpectedly, the MT-null mice were apparently in good health, and the critical biological roles of MT have been questioned. MT seems to be a protective protein produced in response to a variety of stresses. Here, current studies on the protective roles of MT against toxicity of heavy metals and reactive oxygen species are reviewed, and the putative biological functions of MT are discussed.