A [4Fe4S](2+) cluster in the C-terminal domain of the catalytic subunit of the eukaryotic B-family DNA polymerases is essential for the formation of active multi-subunit complexes. Here we use a combination of electrochemical and biochemical methods to assess the redox activity of the [4Fe4S](2+) cluster in Saccharomyces cerevisiae polymerase (Pol) delta, the lagging strand DNA polymerase. We find that Pol delta bound to DNA is indeed redox-active at physiological potentials, generating a DNA-mediated signal electrochemically with a midpoint potential of 113 +/- 5 mV versus NHE. Moreover, biochemical assays following electrochemical oxidation of Pol delta reveal a significant slowing of DNA synthesis that can be fully reversed by reduction of the oxidized form. A similar result is apparent with photooxidation using a DNA-tethered anthraquinone. These results demonstrate that the [4Fe4S] cluster in Pol delta can act as a redox switch for activity, and we propose that this switch can provide a rapid and reversible way to respond to replication stress.