Metals and oxygen are chemically linked in biological systems. Metals and oxygen play important roles in enzymatic reactions, metabolism, and signal transduction; however, metals and oxygen react to form highly toxic oxygen-derived free radical species. In this review we focus on the use of yeast cells, as unicellular eukaryotic model systems, to conduct studies aimed at understanding fundamental mechanisms for the sensation and protective responses to toxic metals and oxygen-derived radicals via the activation of yeast metallothionein gene expression.