During the first billion years of life on the Earth, the environment was anaerobic. Iron and sulphur were plentiful, and they were recruited in the formation of iron-sulphur (Fe-S) clusters within ancient proteins. These clusters provided many enzymes with the ability to transfer electrons; to others they offered a cationic feature that tightly bound oxyanionic and nitrogenous metabolites. Still others acquired a crystallizing surface around which polypeptide could fold to establish a three-dimensional structure. However, the subsequent oxygenation of the Earth's atmosphere by photosynthetic organisms created a threat to cluster-dependent proteins that still has not been fully resolved. By oxidizing environmental iron, oxygen limits its bioavailability, requiring that organisms employ complex schemes with which to satisfy their iron requirement. More directly, oxygen species convert exposed Fe-S clusters to unstable forms that quickly decompose. Some microbes responded to this dilemma by retreating to anaerobic habitats. Others abandoned the use of low-potential electron-transfer pathways, which rely upon the least stable cluster enzymes, and developed antioxidant strategies to protect the remainder. These adjustments were only partially successful: largely because of their reliance upon Fe-S clusters, aerobes remain vulnerable to iron restriction and oxidative stress, features that higher organisms exploit in defending themselves against bacterial pathogens. Thus, the history of Fe-S clusters is an unusual one that has profoundly shaped contemporary microbial ecology.