Metallothionein (MT) is a cysteine-rich, metal-binding protein that plays an important role in the detoxication of heavy metals and in the homeostasis of essential metal ions. Deficiency in MT makes animals highly sensitive to toxicity of some metals, and may predispose to inorganic carcinogenesis. For instance, poor expression of MT in regions of rat prostate is a susceptibility factor in cadmium-induced prostate cancer. Similarly, MT-1/2 null mice, where the major forms of MT are knocked out, are more sensitive than wild-type mice to the carcinogenic effects of cadmium, arsenic, lead, and cisplatin. On the other hand, the carcinogenic potential of nickel is unchanged in MT-1/2 null mice or in MT-1 overexpressing transgenic mice, suggesting a minimal role for this protein in nickel carcinogenesis. Several mechanisms have been proposed for the inhibitory role of MT in inorganic carcinogenesis, including metal sequestration, reduced oxidative stress, adaptation response, acquired apoptosis resistance, and compromised DNA repair. In mice a clear inability to form inclusion bodies is implicated in enhanced lead-induced renal carcinogenesis in MT-1/2 null mice, while downregulation of MT occurs during hepatocarcinogenesis induced by transplacental arsenic. There is a great variation in human MT expression and polymorphisms of the MT gene exist that may affect individual response to toxic metal insult, and poor ability to produce MT in response to metal exposure clearly may predispose individuals to carcinogenesis, by some, but not all, inorganic carcinogens.