Iron-sulfur clusters are prosthetic groups commonly found in proteins that participate in oxidation-reduction reactions and catalysis. Here, we focus on two proteins that contain iron-sulfur clusters, the fumarate nitrate reduction (FNR) protein of Escherichia coli and mammalian iron-responsive-element-binding protein 1 (IRP1), both of which function as direct sensors of oxygen and iron levels. Assembly and disassembly of iron-sulfur clusters is the key to sensing in these proteins and we speculate that iron-sulfur clusters might be found in other regulatory proteins that sense levels of iron and/or oxygen.