The rsmA gene of Streptomyces coelicolor lies directly upstream of the gene encoding the group 3 sigma factor ^M. The RsmA protein is a putative member of the HATPase_c family of anti-sigma factors, but is unusual in that it contains seven cysteine residues. Bacterial two-hybrid studies demonstrate that it interacts specifically with ^M and in vitro studies of the purified proteins by native PAGE and transcription run offs confirmed that they form a complex. Characterization of RsmA revealed that it binds ATP and that, as isolated, contains significant quantities of iron and inorganic sulfide, in equal proportion, with spectroscopic properties characteristic of a [2Fe-2S] cluster-containing protein. Importantly, the interaction between RsmA and ^M is dependent on the presence of the iron-sulfur cluster. We propose a model in which RsmA regulates the activity of ^M. Loss of the cluster, in response to an as yet unidentified signal, activates ^M by abolishing its interaction with the anti-sigma factor. This represents a major extension of the functional diversity of iron-sulfur cluster proteins.