Metals play a dual role in biological systems, serving as essential co-factors for a wide range of biochemical reactions yet these same metals may be extremely toxic to cells. To cope with the stress of increases in environmental metal concentrations, eukaryotic cells have developed sophisticated toxic metal sensing proteins which respond to elevations in metal concentrations. This signal is transmitted to stimulate the cellular transcriptional machinery to activate expression of metal detoxification and homeostasis genes. This review summarizes our current understanding of the biochemical and genetic mechanisms which underlie cellular responses to toxic metals via metalloregulatory transcription factors.