Streptomyces are prevalent producers of clinically used antibiotics, with genomes typically encoding far more secondary metabolites than we can elicit production of in the lab. This is thought to be due to complex environmental niches and the various ecological functions of these molecules. As such, understanding the regulatory mechanisms of these metabolites is vital to improving discovery and production. Two-component systems (2CS) are employed by Streptomyces to sense and respond to their environment. These regulatory systems are known to be implicated in the production of various antibiotics in several strains. The CutRS 2CS which is highly conserved controls actinorhodin production in S. coelicolorand chloramphenicol production in S. venezuelae. ChIP-seq and proteomics showing the in-vivo DNA binding and the differentially produced proteins suggest a link between secretion stress and CutRS. Bioinformatic analysis has determined the extracellular sensor domain of all CutS homologues contain dual cysteine residues which are likely important in sensing disulphide bond formation and folding of secreted proteins. We hypothesise that loss of CutRS induces actinorhodin production because this molecule can oxidise cysteine residues and rescue the defect in protein folding and that actinorhodin is produced, not to kill other bacteria, but as part of the host secretion stress response. This new understanding of the mechanism of CutRS and bioinformatic analysis showing the prevalence and genomic location of 2CS leads us to believe that manipulation of these conserved systems could hold the key to unlocking the production of useful secondary metabolites from cryptic biosynthetic gene clusters