Iron-Sulfur (Fe-S) cofactors containing proteins are key players in a plethora of biological pathways. Despite their essential roles, and because of the vulnerability of Fe/S cofactors, these proteins are not only highly prone to stress induced damage but also are internal “stress inducers” themselves as they can release free Fe2+ which produces toxic radicals by reacting with oxygen. Cells have thus designed multiple intricate ways to maintain Fe-S proteins integrity and to avoid Fe-S proteins to become the Achilles’ heel of the cell. A major stress defense mechanism is the fine control of Fe/S biogenesis under stress conditions. Remarkably, the model bacterium E. coli has the two most conserved Fe-S biogenesis systems, Isc and Suf that share biochemical features, yet differ under many structural and genetic aspects. E. coli thus constitutes an ideal model for the study of Fe-S biogenesis. The main focus of my project is to understand the mechanisms underlying the control of Fe-S biogenesis under stress in E. coli. To do so, this project takes advantage of technological advances to look at the dynamics of Fe-S biogenesis in the face of stress conditions. In addition, preliminary data I gathered during my post-doctoral training strongly suggest that the ensemble of Fe-S biogenesis system is regulated by small regulatory RNAs (sRNAs). In the last decade, sRNAs have emerged as major players in the control of gene expression in all kingdoms of life. Thus, an important part of this project will be devoted to identifying and characterizing the sRNAs regulating Fe-S biogenesis in response to stress. This discovery is unprecedented and could lead to a major breakthrough. The project presented herein thus constitutes an innovative and ambitious study that sits at the crossroad of two domains of investigation, Fe-S biogenesis in vivo and sRNA regulation, of utmost importance. A main objective of this project is to enable me to create my own group in the next five years.