The therapeutic uses of antineoplastic agents are limited primarily due to two reasons: the drugs cause toxicity to non-malignant tissues and malignant tissues develop resistance to the toxic effects of the drugs. Many clinically effective antineoplastic agents are electrophilic and interact either covalently or non-covalently with genomic DNA. Although the interactions with DNA are generally thought to mediate their cytotoxicity, these drugs may also react with other cellular nucleophiles. Recent efforts have focused on understanding the role of thiol-rich proteins, especially metallothioneins, in determining the response of cells and tissues to specific classes of cytotoxic antineoplastic agents. Studies with cells in culture demonstrate that increases in metallothionein can afford protection against the toxic actions of both alkylating agents and cis-diamminedichloroplatinum (cisplatin). Tumors rich in metallothionein have also been reported to exhibit resistance to alkylating agents and cisplatin when grown in vivo. Pretreatment of mice with heavy metals, such as Bi salts, has been found to decrease the lethality and the renal and gastrointestinal toxicity associated with cisplatin. Some investigators have reported that the lethality of doxorubicin and its toxicity to the heart and bone marrow also have been significantly decreased by pretreatment of mice with Bi salts. We summarize these recent studies and discuss the proposition that intracellular metallothioneins may have a role in determining the toxicity of anticancer agents to non-malignant tissues.