AbstractIt has been suggested that metallothioneins, discovered about 45 years ago, play a central role in heavy metal metabolism and detoxification, and in the management of various forms of stress. The metal‐regulatory transcription factor‐1 (MTF‐1) was shown to be essential for basal and heavy metal‐induced transcription of the stress‐responsive metallothionein‐I and metallothionein‐II. Recently it has become obvious that MTF‐1 has further roles in the transcriptional regulation of genes induced by various stressors and might even contribute to some aspects of malignant cell growth. Furthermore, MTF‐1 is an essential gene, as mice null‐mutant for MTF‐1 die in utero due to liver degeneration. We describe here the state of knowledge on the complex activation of MTF‐1, and propose a model with MTF‐1 as an interconnected cellular stress‐sensor protein involved in heavy metal metabolism, hepatocyte differentiation and detoxification of toxic agents. BioEssays 23:1010–1017, 2001. © 2001 John Wiley & Sons, Inc.