The rapid and robust induction of metallothioneins (MT)-I and II by a variety of inducers that include heavy toxic metals, reactive oxygen species, and different types of stress provide a useful system to study the molecular mechanisms of this unique induction process. The specific expression of MT-III in the brain and of MT-IV in the squamous epithelium of skin and tongue offers a unique opportunity to identify and characterize the tissue-specific factors involved in their expression. Studies using transgenic mice that overexpress MTs or MT null mice have revealed the role of MT in the protection of cells against numerous tissue-damaging agents such as reactive oxygen species. The primary physiological function of these proteins, however, remains an enigma. Considerable advances have been made in the identification of the cis-acting elements that are involved in the constitutive and induced expression of MT-I and MT-II. By contrast, only one key trans-activating factor, namely MTF-1, has been extensively characterized. Studies on the epigenetic silencing of MT-I and MT-II by promoter hypermethylation in some cancer cells have posed interesting questions concerning the functional relevance of MT gene silencing, the molecular mechanisms of MT suppression in these cells, particularly chromatin modifications, and the characteristics of the repressors.